CoChat
Sign Up
Cited by 1,019Lung Cancer Treatments and MutationsCancer Genomics and DiagnosticsLung Cancer Research Studies

Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy

Open access
Skoulidis, Ferdinandos, Heymach, John V.·2019·Nature Reviews Cancer
DOI 10.1038/s41568-019-0179-8PMC PMC7043073
Open this paper in CoChat — free account

Abstract

The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease. However, recent studies have revealed considerable phenotypic diversity downstream of tumour-initiating oncogenes. Co-occurring genomic alterations, particularly in tumour suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumour cell-intrinsic and non-cell-autonomous cancer hallmarks. In this Review, we discuss the impact of co-mutations on the pathogenesis, biology, microenvironmental interactions and therapeutic vulnerabilities of non-small-cell lung cancer and assess the challenges and opportunities that co-mutations present for personalized anticancer therapy, as well as the expanding field of precision immunotherapy.

Integrity signals

Registry

Crossref · 10.1038/s41568-019-0179-8

Cites

193 of 193 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 317 cited sources checked · 0 supported · 0 flagged

  • Premisereasoning

    NSCLCs driven by the same dominant oncogenic alteration can vary considerably in histological appearance and immunohistochemical profile.

    “NSCLCs driven by the same dominant oncogenic alteration can vary considerably in their histological appearance and immunohistochemical profile.”
    Quote in the paperSubstantial claim
  • Premisereasoning

    There is mounting evidence that substantial molecular and clinical heterogeneity exists within oncogenic driver-defined subgroups of NSCLC.

    “There is mounting evidence that substantial molecular and clinical heterogeneity exists within oncogenic driver-defined subgroups of NSCLC (“intra-driver heterogeneity”).”
    Quote in the paperSubstantial claim
  • Premisenone given

    Recent studies show considerable phenotypic diversity downstream of tumor-initiating oncogenes.

    “recent studies have revealed considerable phenotypic diversity downstream of tumor-initiating oncogenes”
    Quote in the paperSubstantial claim
  • Interpretationnone given

    Co-occurring genomic alterations, especially in tumor suppressor genes like TP53 and LKB1, are core determinants of molecular and clinical heterogeneity in oncogene-driven lung cancer subgroups, acting through tumor cell-intrinsic and non-cell-autonomous hallmarks.

    “Co-occurring genomic alterations, particularly in tumor suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumor cell-intrinsic and non-cell-autonomous cancer hallmarks.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Accumulating evidence indicates substantial clinical heterogeneity within oncogenic-driver defined NSCLC subgroups that the single oncogenic driver model does not fully explain.

    “accumulating evidence points towards the existence of substantial clinical heterogeneity within oncogenic-driver defined NSCLC subgroups that is currently incompletely accounted for by the single oncogenic driver model”
    Quote in the paperNot a substantial claim
  • May combine two claims. 62
  • Classified as probably not a substantial claim. 3
  • The quote only partly states this claim. 2

  • May combine two claims.

    Premisecitation

    TP53 mutations are under-represented among KRAS-mutant LUAD compared to other oncogene-driven subgroups, yet p53 inactivation is common and impactful in KRAS-mutant LUAD.

    “For example, mutations in TP53 (which encodes p53) are under-represented among KRAS-mutant LUAD compared to other oncogene-driven subgroups, yet p53 inactivation is common and impactful in KRAS-mutant LUAD67–71.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

      Not checked in the free run.

    • cites [68] Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018). This study identifies inactivating LKB1 genomic alterations as a major driver of de novo resistance to PD-1 axis blockade in KRAS -mutant LUAD. source

      Not checked in the free run.

    • cites [69] Johnson, L. et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature 410, 1111–1116 (2001). source

      Not checked in the free run.

    • cites [70] Jackson, E. L. et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 65, 10280–10288 (2005). source

      Not checked in the free run.

    • cites [71] Fisher, G. H. et al. Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumour suppressor genes. Genes Dev. 15, 3249–3262 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In RET-rearranged NSCLC, non-KIF5B-RET fusions are associated with significantly higher response rates to RXDX-105 but not to LOXO-292.

    “Similarly, in RET-rearranged NSCLC, non-KIF5B-RET fusions have been associated with significantly higher response rates to RXDX-105 (a RET and BRAF inhibitor) but not to the potent and selective RET inhibitor LOXO-29250.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Drilon, A. et al. A phase I/Ib trial of the VEGFR-sparing multikinase RET inhibitor RXDX-105. Cancer Discov. 9, 384–395 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Distinct KRAS mutant alleles differentially engage downstream effectors: KRASG12C or KRASG12V preferentially activate RALA or RALB signaling, and KRASG12D triggers increased PI3K-AKT and MAPK/ERK pathway activation.

    “Finally, distinct KRAS mutant alleles differentially engage downstream effectors with KRASG12C or KRASG12V preferentially activating RALA or RALB signaling and KRASG12D triggering increased PI3K–AKT and MAPK/ERKpathway activation51.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Ihle, N. T. et al. Effect of KRAS oncogene substitutions on protein behavior: implications for signaling and clinical outcome. J. Natl Cancer. Inst. 104, 228–239 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inter- and intra-driver heterogeneity are also evident after PD-1 or PD-L1 inhibitor treatment, with only about 20% of unselected NSCLC patients deriving durable clinical benefit.

    “Inter- and intra-driver heterogeneity are also evident following treatment with inhibitors of the immune checkpoint molecules PD-1 or PD-L1, with only ~20% of unselected NSCLC patients deriving durable clinical benefit38–43.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [38] Borghaei, H. et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N. Engl. J. Med. 373, 1627–1639 (2015). source

      Not checked in the free run.

    • cites [39] Carbone, D. P. et al. First-line nivolumab in stage iv or recurrent non-small-cell lung cancer. N. Engl. J. Med. 376, 2415–2426 (2017). source

      Not checked in the free run.

    • cites [40] Fehrenbacher, L. et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet 387, 1837–1846 (2016). source

      Not checked in the free run.

    • cites [41] Herbst, R. S. et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet 387, 1540–1550 (2016). source

      Not checked in the free run.

    • cites [42] Horn, L. et al. Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J. Clin. Oncol. 35, 3924–3933 (2017). source

      Not checked in the free run.

    • cites [43] Rittmeyer, A. et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet 389, 255–265 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Early oncogenic events may channel tumor evolution towards distinct trajectories and influence the likelihood of positive or negative selection of subsequent genomic alterations.

    “This further suggests that early oncogenic events may channel tumor evolution towards distinct trajectories and influence the likelihood of positive or negative selection of subsequent genomic alterations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Co-selection of oncogenic alterations implies functional co-operation that converges on improved fitness, whereas mutual exclusivity indicates redundancy or antagonism.

    “From an evolutionary standpoint, co-selection of oncogenic alterations implies functional co-operation that converges on improved fitness, whereas mutual exclusivity indicates redundancy (potentially manifesting as soft exclusivity) or antagonism (resulting in more strict patterns of mutual exclusivity due to deleterious effects of the combined alterations)63, 64.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] Mina, M. et al. Conditional selection of genomic alterations dictates cancer evolution and oncogenic dependencies. Cancer Cell 32, 155–168 (2017). This study describes a novel algorithmic approach for assessment of cancer evolutionary dependencies and is the most comprehensive pancancer analysis of co-alteration patterns reported to date. source

      Not checked in the free run.

    • cites [64] Campbell, P. J. Cliques and schisms of cancer genes. Cancer Cell 32, 129–130 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In first-line targeted therapy trials for oncogene-addicted NSCLC, objective response rates typically range from 50% to 83%, complete responses are rare, and some patients show de novo resistance.

    “Across clinical trials of first-line targeted therapy for oncogene-addicted subgroups of NSCLC, rates of objective response [G] typically range between 50% and 83% and complete responses [G] are rare; in addition, some patients exhibit de novo resistance16–26, 28–32, 35.”
    Quote in the paperSubstantial claim0 of 10 sources checked
    • cites [16] Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009). source

      Not checked in the free run.

    • cites [17] Zhou, C. et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 12, 735–742 (2011). source

      Not checked in the free run.

    • cites [18] Rosell, R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13, 239–246 (2012). source

      Not checked in the free run.

    • cites [19] Yang, J. C. et al. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 16, 141–151 (2015). source

      Not checked in the free run.

    • cites [20] Soria, J. C. et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N. Engl. J. Med. 378, 113–125 (2018). source

      Not checked in the free run.

    • cites [21] Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017). source

      Not checked in the free run.

    • cites [22] Mok, T. S. et al. Improvement in overall survival in a randomized study that compared dacomitinib with gefitinib in patients with advanced non-small-cell lung cancer and EGFR-activating mutations. J. Clin. Oncol. 36, 2244–2250 (2018). source

      Not checked in the free run.

    • cites [23] Peters, S. et al. Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer. N. Engl. J. Med. 377, 829–838 (2017). source

      Not checked in the free run.

    • cites [24] Solomon, B. J. et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N. Engl. J. Med. 371, 2167–2177 (2014). source

      Not checked in the free run.

    • cites [25] Soria, J. C. et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. Lancet 389, 917–929 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EGFR exon 20 in-frame insertion mutants are resistant to all currently FDA-approved EGFR TKIs due to steric hindrance, but are sensitive to poziotinib in vitro and in vivo.

    “Furthermore, EGFR exon 20 in-frame insertion mutants are recalcitrant to all currently FDA-approved EGFR TKIs due to insertion-imposed steric hindrance of the drug binding pocket, but exhibit sensitivity to poziotinib - a smaller and more flexible inhibitor - in vitro and in vivo46, 47.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [46] Robichaux, J. P. et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nat. Med. 24, 638–646 (2018). source

      Not checked in the free run.

    • cites [47] Riess, J. W. et al. Diverse EGFR exon 20 insertions and co-occurring molecular alterations identified by comprehensive genomic profiling of NSCLC. J. Thorac. Oncol. 13, 1560–1568 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    EML4-ALK variant 3 is associated with more frequent secondary resistance mutations, including G1202R, compared to variant 1, and consequently longer progression-free survival with lorlatinib.

    “In addition, EML4-ALK variant 3 was associated with more frequent secondary resistance mutations (including the G1202R solvent front mutation) compared to EML4-ALK variant 1 and, consequently, longer progression-free survival with the 3rd generation ALK inhibitor lorlatinib, that is active against the EML4-ALKG1202R mutation49.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Lin, J. J. et al. Impact of EML4-ALK variant on resistance mechanisms and clinical outcomes in ALK-positive lung cancer. J. Clin. Oncol. 36, 1199–1206 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Intra-driver molecular diversity translates into heterogeneous clinical behavior and variable sensitivity to anticancer therapies.

    “Most importantly, overwhelming evidence indicates that intra-driver molecular diversity translates into heterogeneous clinical behavior and variable sensitivity to anticancer therapies.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Enrichment for specific oncogenic drivers occurs within distinct molecular subtypes of LUAD, but cluster membership typically transcends initiating oncogenes.

    “Enrichment for specific oncogenic drivers has been observed within distinct subtypes, however cluster membership typically transcends initiating oncogenes, thus providing further evidence for intra-driver molecular diversity34.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    Distinct KRAS alleles were not differentially distributed between the three clusters, with the exception of enrichment for KRASG12D in the KC subgroup in some cohorts.

    “Notably, distinct KRAS alleles were not differentially distributed between the three clusters – with the exception of enrichment for KRASG12D in the KC subgroup in some cohorts.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KEAP1 loss results in increased cellular proliferation in vivo and an altered metabolic profile characterized by increased glucose-derived carbon flux towards the pentose phosphate and serine-glycine biosynthetic pathways with enhanced dependence on glutaminolysis for TCA cycle anaplerosis, a dependence further enhanced by co-occurring LKB1 alterations.

    “At the cellular level KEAP1 loss results in increased cellular proliferation in vivo and an altered metabolic profile characterized by increased glucose-derived carbon flux towards the pentose phosphate and serine–glycine biosynthetic pathways93–95 with enhanced dependence on glutaminolysis for tricarboxylic acid (TCA) cycle anaplerosis92, a dependence that is further enhanced by co-occurring LKB1”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [92] Babur, O. et al. Systematic identification of cancer driving signalling pathways based on mutual exclusivity of genomic alterations. Genome Biol. 16, 45 (2015). source

      Not checked in the free run.

    • cites [93] Romero, R. et al. Keap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis. Nat. Med. 23, 1362–1368 (2017). source

      Not checked in the free run.

    • cites [94] Singh, A. et al. Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumourigenesis. J. Clin. Invest. 123, 2921–2934 (2013). source

      Not checked in the free run.

    • cites [95] DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumourigenesis. Nature 475, 106–109 (2011). source

      Not checked in the free run.

    • cites [96] DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small-cell lung cancer. Nat. Genet. 47, 1475–1481 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    A second cluster (KL) was characterized by co-mutations or genomic loss in LKB1 and was further enriched in somatic mutations in KEAP1 and ATM.

    “whereas co-mutations or genomic loss in LKB1 (also known as STK11) were a hallmark of the second cluster (referred to as KL), that was further enriched in somatic mutations in KEAP1 and ATM.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MHC class I genotype of individual patients imposes restrictions on the tumor mutational landscape and predicts selection of distinct driver mutations.

    “For example, the major histocompatibility complex (MHC) class I genotype of individual patients was demonstrated to impose restrictions on the tumor mutational landscape and predict for selection of distinct driver mutations80.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Marty, R. et al. MHC-I genotype restricts the oncogenic mutational landscape. Cell 171, 1272–1283 (2017). e15. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    The significance of co-occurrence for individual pairs of genetic alterations varies depending on the size of the clinical cohort, the number of possible interactions surveyed, and the sequencing platform.

    “The significance of co-occurrence for individual pairs of genetic alterations varies depending on the size of the clinical cohort, the number of possible interactions that are surveyed and the sequencing platform.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Targeting clonal events is more likely to yield sustained responses; clonal events are more likely to result in primary resistance, although both clonal and sub-clonal events can contribute to clinical resistance.

    “In addition, targeting clonal events is more likely to yield sustained responses; although both clonal and sub-clonal events can contribute to clinical resistance, clonal events are more likely to result in primary resistance.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Loss of Lkb1 results in epigenetic reprogramming and an expanded tumor histological repertoire, with high incidence of squamous or adenosquamous carcinomas, in agreement with data supporting enrichment of LKB1 mutations in human adenosquamous NSCLC.

    “In addition, loss of Lkb1 results in epigenetic reprogramming and an expanded tumor histological repertoire, with high incidence of squamous or adenosquamous carcinomas, in agreement with data supporting enrichment of LKB1 mutations in human adenosquamous NSCLC84–86.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [84] Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007). source

      Not checked in the free run.

    • cites [85] Li, F. et al. LKB1 inactivation elicits a redox imbalance to modulate non-small cell lung cancer plasticity and therapeutic response. Cancer Cell 27, 698–711 (2015). source

      Not checked in the free run.

    • cites [86] Zhang, H. et al. Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb repressive complex 2. Nat. Commun. 8, 14922 (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Mutations in TP53 and inactivation of CDKN2A, CDKN2B or combined CDKN2A/CDKN2B loss are common and functionally relevant co-alterations, although they are not enriched in KRAS-mutant compared to other oncogene-driven subgroups.

    “Mutations in TP53 and inactivation of CDKN2A, CDKN2B or combined CDKN2A/CDKN2B loss due to bi-allelic deletion, are common and functionally relevant co-alterations, although they are not enriched in KRAS-mutant compared to other oncogene-driven subgroups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Somatic deletion of Lkb1 is insufficient for initiation of lung carcinogenesis in mice as a singular event but dramatically accelerates KrasG12D-driven carcinogenesis and fosters early metastatic dissemination.

    “Somatic deletion of Lkb1 is insufficient for initiation of lung carcinogenesis in mice as a singular event but dramatically accelerates KrasG12D-driven carcinogenesis and fosters early metastatic dissemination84.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Somatic mutations in LKB1 and KEAP1 significantly co-occur with mutant KRAS and with each other in NSCLC.

    “Somatic mutations in LKB1 and KEAP1 significantly co-occur with mutant KRAS and with each other in NSCLC15, 59, 63, 91.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

      Not checked in the free run.

    • cites [59] Jordan, E. J. et al. prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 7, 596–609 (2017). This article and Frampton et al. (2015) are the largest reported studies of comprehensive genomic profiling in patients with advanced LUAD. source

      Not checked in the free run.

    • cites [63] Mina, M. et al. Conditional selection of genomic alterations dictates cancer evolution and oncogenic dependencies. Cancer Cell 32, 155–168 (2017). This study describes a novel algorithmic approach for assessment of cancer evolutionary dependencies and is the most comprehensive pancancer analysis of co-alteration patterns reported to date. source

      Not checked in the free run.

    • cites [91] Jaramillo, M. C. & Zhang, D. D. The emerging role of the Nrf2-Keap1 signalling pathway in cancer. Genes Dev. 27, 2179–2191 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the conditional KrasG12D/+;Trp53Fl/FL mouse model, loss of Keap1 increases both tumor burden and the percent of high-grade lesions, pointing towards roles in both tumor initiation and progression.

    “In the conditional KrasG12D/+;Trp53Fl/FL mouse model, loss of Keap1 increases both tumor burden and the percent of high-grade lesions, pointing towards roles in both tumor initiation and progression92.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Babur, O. et al. Systematic identification of cancer driving signalling pathways based on mutual exclusivity of genomic alterations. Genome Biol. 16, 45 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    In myeloproliferative disorders, the order in which JAK2 and TET2 mutations arise can affect age of disease onset, influence whether the disease manifests as polycythemia vera versus essential thrombocythemia, and result in different propensities for thrombosis.

    “For example in myeloproliferative disorders, the order in which mutations in JAK2 and TET2 arise in hematopoietic stem and progenitor cells can affect age of disease onset, influence the likelihood of the disease manifesting as polycythemia vera versus essential thrombocythemia and result in different propensities for development of thrombosis75, 76.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [75] Ortmann, C. A. et al. Effect of mutation order on myeloproliferative neoplasms. N. Engl. J. Med. 372, 601–612 (2015). source

      Not checked in the free run.

    • cites [76] Swanton, C. Cancer evolution constrained by mutation order. N. Engl. J. Med. 372, 661–663 (2015). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Early clonal events are more likely to impact core cancer hallmarks that are critical for tumor initiation.

    “Early clonal events are more likely to impact core cancer hallmarks that are critical for tumor initiation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In the TRACERx study, multiregion sequencing of 100 early-stage NSCLCs measured the extent of clonal driver events (1-18 in LUAD and 1-14 in LUSC) and sub-clonal driver events (0-10 in LUAD and 0-12 in LUSC) and established a catalog of clonal alterations.

    “In the landmark TRACERx study, multiregion sequencing of 100 early-stage NSCLCs provided a measure of the extent of clonal driver events (1–18 in LUAD and 1–14 in LUSC) and sub-clonal driver events (0–10 in LUAD and 0–12 in LUSC) and established a catalog of clonal alterations74.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017). This landmark study establishes a census of clonal and subclonal alterations in early-stage NSCLC and identifies copy number heterogeneity as an independent predictor of short relapse-free survival following surgical resection. source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    A third cluster (KC) was significantly enriched for bi-allelic inactivation of the CDKN2A/CDKN2B locus and was defined by lack of NKX2-1 expression.

    “Bi-allelic inactivation of the CDKN2A/CDKN2B locus was significantly enriched in the third cluster (referred to as KC), that was defined by lack of NKX2–1 expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KL NSCLC cells exhibit increased dependence on dTTP synthesis and rely on an unorthodox pathway of pyrimidine biosynthesis that utilizes mitochondrially generated carbamoyl phosphate.

    “Furthermore, KL NSCLC cells exhibit increased dependence on dTTP synthesis and rely on an unorthodox pathway of pyrimidine biosynthesis that utilizes mitochondrially generated carbamoyl phosphate88, 89.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [88] Liu, Y. et al. Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. Cancer Discov. 3, 870–879 (2013). source

      Not checked in the free run.

    • cites [89] Kim, J. et al. CPS1 maintains pyrimidine pools and DNA synthesis in KRAS/LKB1-mutant lung cancer cells. Nature 546, 168–172 (2017). This article identifies a co-mutation-specific metabolic dependence of KRAS ; LKB1 co-altered cells on the urea cycle enzyme CPS1 in order to maintain pyrimidine pools. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Classical mutations in PIK3CA occur within APOBEC deaminase trinucleotide motifs and are enriched in tumors with a high APOBEC mutational footprint.

    “Certain recurrent oncogenic mutations, for example classical mutations in PIK3CA (which encodes a catalytic subunit of PI3K), occur within APOBEC deaminase trinucleotide motifs and are enriched in tumors with a high APOBEC mutational footprint77.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [77] Henderson, S., Chakravarthy, A., Su, X., Boshoff, C. & Fenton, T. R. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumour development. Cell Rep. 7, 1833–1841 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TP53 and RB1 co-mutations mark the earliest ancestors of EGFR-mutant LUAD that transform to small cell carcinoma following exposure to EGFR TKIs and dramatically increase the risk of small cell transformation, although loss of RB1 is insufficient to directly induce neuroendocrine trans-differentiation.

    “TP53 and RB1 co-mutations mark the earliest ancestors of EGFR-mutant LUAD that transform to small cell carcinoma following exposure to EGFR TKIs and dramatically increase the risk of small cell transformation, although loss of RB1 is insufficient to directly induce neuroendocrine trans-differentiation.117–119.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [117] Jakobsen, J. N., Santoni-Rugiu, E., Grauslund, M., Melchior, L. & Sorensen, J. B. Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment. Oncotarget 9, 26195–26208 (2018). source

      Not checked in the free run.

    • cites [118] Lee, J. K. et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J. Clin. Oncol. 35, 3065–3074 (2017). This article reports that pre-existing co-alterations in TP53 and RB1 can predict transformation to small-cell carcinoma as a mechanism of acquired resistance to EGFR TKI therapy in EGFR -mutant LUAD. source

      Not checked in the free run.

    • cites [119] Niederst, M. J. et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat. Commun. 6, 6377 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy.

    “In keeping with a more complex genomic landscape and a larger burden of clonal or sub-clonal co-drivers, multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy72, 73, 111–116.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

      Not checked in the free run.

    • cites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source

      Not checked in the free run.

    • cites [111] Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014). source

      Not checked in the free run.

    • cites [112] Canale, M. et al. Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. Clin. Cancer Res. 23, 2195–2202 (2017). source

      Not checked in the free run.

    • cites [113] Sato, S. et al. Impact of concurrent genomic alterations detected by comprehensive genomic sequencing on clinical outcomes in East-Asian patients with EGFR-mutated lung adenocarcinoma. Sci. Rep. 8, 1005 (2018).

      Not checked in the free run.

    • cites [114] VanderLaan, P. A. et al. Mutations in TP53, PIK3CA, PTEN and other genes in EGFR mutated lung cancers: Correlation with clinical outcomes. Lung Cancer 106, 17–21 (2017). source

      Not checked in the free run.

    • cites [115] Labbe, C. et al. Prognostic and predictive effects of TP53 co-mutation in patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Lung Cancer 111, 23–29 (2017). source

      Not checked in the free run.

    • cites [116] Kim, Y. et al. Concurrent genetic alterations predict the progression to target therapy in EGFR-mutated advanced nsclc. J. Thora.c Oncol. 14, 193–202 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Potentiation of cellular anabolic, antioxidant and detoxification pathways collectively support the aggressive clinical phenotype of KEAP1-mutant NSCLC, concordant with its role as an independent negative prognostic indicator.

    “Potentiation of cellular anabolic, antioxidant and detoxification pathways collectively support the aggressive clinical phenotype of KEAP1-mutant NSCLC that is concordant with its role as an independent negative prognostic indicator92, 99.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [92] Babur, O. et al. Systematic identification of cancer driving signalling pathways based on mutual exclusivity of genomic alterations. Genome Biol. 16, 45 (2015). source

      Not checked in the free run.

    • cites [99] Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TP53 mutations are mostly truncal events that occur early during tumor evolution and prior to whole genome doubling, and are frequently accompanied by truncal loss of heterozygosity at the TP53 locus, indicating strong selective pressure for complete TP53 inactivation in early stage LUADs.

    “TP53 mutations are mostly truncal events (present in all geographically distinct segments of the tumor) that occur early during tumor evolution and prior to whole genome doubling, and are frequently accompanied by truncal loss of heterozygosity at the TP53 locus, indicating strong selective pressure for complete TP53 inactivation in early stage LUADs103.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a p53-proficient setting, bi-allelic loss of Atm is tolerated but does not promote KrasG12D-initiated neoplasia.

    “In a p53-proficient setting, bi-allelic loss of Atm is tolerated but does not promote KrasG12D-initiated neoplasia.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [104] Nahar, R. et al. Elucidating the genomic architecture of Asian EGFR-mutant lung adenocarcinoma through multi-region exome sequencing. Nat. Commun. 9, 216 (2018). This article provides a comprehensive evaluation of the clonal and subclonal genomic landscape of early-stage EGFR -mutant LUAD in patients of Asian descent. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Tumors bearing co-mutations in TP53 exhibit higher degrees of copy number genomic instability (aneuploidy) and a higher somatic mutation burden, both on the trunk and in the branches of the tumor phylogenetic tree.

    “Furthermore, tumors bearing co-mutations in TP53 exhibit higher degrees of copy number genomic instability (aneuploidy), and a higher somatic mutation burden, both on the trunk and in the branches of the tumor phylogenetic tree103.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The selective pressure for p53 inactivation is most critical in aggressive, high-grade lesions with high ERK signaling, whereas p53-mediated signaling is minimal in low-grade adenomas.

    “Notably, the selective pressure for p53 inactivation is most critical in aggressive, high-grade lesions that exhibit high levels of ERK signaling, whereas engagement of p53-mediated signaling is minimal in low-grade adenomas, thus highlighting stage and signal intensity - dependent patterns of co-operativity100–102.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [100] Arbour, K. C. et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin. Cancer Res. 24, 334–340 (2018). source

      Not checked in the free run.

    • cites [101] Feldser, D. M. et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572–575 (2010). source

      Not checked in the free run.

    • cites [102] Junttila, M. R. et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468, 567–571 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATM haplo-insufficiency has not been convincingly established in human LUAD, where there is evidence for complete lack of ATM expression by immunohistochemistry in a significant proportion of LUAD.

    “However, ATM haplo-insufficiency has not been convincingly established yet in human LUAD, where there is evidence for complete lack of ATM expression by immunohistochemistry in a significant proportion of LUAD105.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Schmitt, A. et al. ATM deficiency is associated with sensitivity to PARP1- and ATR inhibitors in lung adenocarcinoma. Cancer Res. 77, 3040–3056 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Somatic genomic alterations in CDKN2A and CDKN2B are observed in ~20% and ~12% of metastatic KRAS-mutant NSCLC respectively, and bi-allelic loss of the CDKN2A/CDKN2B locus is a hallmark of the KC subgroup.

    “Somatic genomic alterations in CDKN2A [encoding the p16 and p14ARF (p19ARF in the mouse) tumor suppressors] and CDKN2B (encoding p15) are observed in ~20% and ~12% of metastatic KRAS-mutant NSCLC respectively and bi-allelic loss of the CDKN2A/CDKN2B locus is a hallmark of the KC subgroup15, 67.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

      Not checked in the free run.

    • cites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Selection against complete ATM inactivation may explain the mutual exclusivity of ATM and TP53 mutations in human LUAD as well as the enrichment of ATM mutations in the KL subgroup.

    “Selection against complete ATM inactivation may explain the mutual exclusivity of ATM and TP53 mutations in human LUAD as well as the enrichment of ATM mutations in the KL subgroup67.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [67] Skoulidis, F. et al. Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov. 5, 860–877 (2015). This article identifies co-alterations in LKB1, TP53 and CDKN2A/CDKN2B as key determinants of the molecular diversity of KRAS -mutant LUAD and is the first report linking LKB1 co-mutations with a non-T cell-inflamed tumour immune microenvironment in LUAD. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Both isolated Cdkn2a loss and combined Cdkn2a/Cdkn2b inactivation accelerate KrasG12D-driven lung carcinogenesis and promote loco-regional metastatic spread, but combined loss of p16, p19ARF and p15 elicits a more marked phenotype than Cdkn2a loss alone with enhanced cellular proliferation, frequent loss of NKX2-1 expression, up-regulation of HMGA2, increased burden of poorly differentiated high-g

    “Both isolated Cdkn2a loss (leading to inactivation of p16 and p19ARF) as well as combined Cdkn2a/Cdkn2b inactivation accelerate KrasG12D-driven lung carcinogenesis and promote loco-regional metastatic spread but combined loss of p16, p19ARF and p15 elicits a more marked phenotype than Cdkn2a loss alone with enhanced cellular proliferation, frequent loss of NKX2–1 expression and up-regulation of”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] Rogers, Z. N. et al. Mapping the in vivo fitness landscape of lung adenocarcinoma tumour suppression in mice. Nat. Genet. 50, 483–486 (2018). This study describes a novel in vivo platform for the rapid evaluation of the functional impact of co-occurring alterations in GEMMs of Kras -mutant LUAD. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The spectrum of enriched genomic co-alterations in advanced EGFR-mutant LUAD is dominated by recurrent mutations in TP53 (54.6%-64.6%), RB1 (9.6%-10.33%), CTNNB1 (5.3%-9.6%), and PIK3CA (9%-12.4%), as well as amplifications involving EGFR (22%-25.5%), NKX2-1 (12.2%-16.7%), CDK4 (7%-10%), CDK6 and CCNE1.

    “The spectrum of enriched genomic co-alterations in advanced EGFR-mutant LUAD is dominated by recurrent mutations in a core set of genes including TP53 (54.6% % - 64.6%), RB1 (9.6%−10.33%), CTNNB1 (which encodes β-catenin; 5.3%−9.6%), and PIK3CA (9%−12.4%) as well as amplifications involving EGFR itself (22% - 25.5%), NKX2–1 (12.2% - 16.7%), CDK4 (7%−10%), CDK6 and CCNE115, 72, 73 (Figure 2).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

      Not checked in the free run.

    • cites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

      Not checked in the free run.

    • cites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    KC tumors are characterized by lack of NKX2-1 expression and frequent activation of a gastrointestinal transcriptional program, enrichment for the KrasG12D mutation, and poor prognosis.

    “KC tumors are characterized by lack of NKX2–1 expression and frequent activation of a gastrointestinal transcriptional program (manifesting histologically as invasive mucinous carcinoma in some cases), enrichment for the KrasG12D mutation and poor prognosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mutations in PIK3CA and CTNNB1 are more frequent in advanced stage tumors compared with early stage LUADs, whereas alterations in TP53, RB1 and NKX2-1 appear to occur with comparable frequencies in early- and advanced-stage tumors.

    “Mutations in PIK3CA and CTNNB1 are more frequent in advanced stage tumors compared with early stage LUADs, pointing towards functional roles in malignant progression and metastasis, whereas alterations in TP53 (62.5%), RB1 (9.5 −12.5%) and NKX2–1 (12.5%) appear to occur with comparable frequencies in early- and advanced-stage tumors15, 34, 72, 73.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [15] Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. Cancer Discov. 5, 850–859 (2015). source

      Not checked in the free run.

    • cites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source

      Not checked in the free run.

    • cites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

      Not checked in the free run.

    • cites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    NKX2-1 functions as a lineage survival oncogene in EGFR-mutant NSCLC, plausibly explaining its preferential amplification in this subgroup.

    “Thus, the function of NKX2–1 as a lineage survival oncogene in EGFR-mutant NSCLC provides a plausible explanation for its preferential amplification in this oncogenic subgroup.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a mouse LUAD model carrying compound EgfrL858R/T790M mutations, Ctnnb1 deletion lowered tumor burden, which suggests non-redundant roles in initiating tumors.

    “in a mouse LUAD model driven by compound EgfrL858R/T790M mutations genetic deletion of Ctnnb1 reduced tumor burden indicating non-redundant functions in tumor initiation122”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [122] Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genomic alterations, most commonly deletion events, in CDKN2A and CDKN2B are observed in ~24.6% and 20.2% of EGFR-mutant tumors and these alterations are typically truncal.

    “Similarly, genomic alterations –most commonly deletion events - in the CDKN2A and CDKN2B genes are observed in ~24.6% and 20.2% of EGFR-mutant tumors and these alterations are typically truncal, further underscoring the significance of G1/S checkpoint dysregulation in the early stages of lung carcinogenesis driven by mutant EGFR72, 73, 103.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [72] Yu, H. A. et al. Concurrent alterations in EGFR-mutant lung cancers associated with resistance to EGFR kinase inhibitors and characterization of MTOR as a mediator of resistance. Clin. Cancer Res. 24, 3108–3118 (2018). This article describes the clinical impact of co-occurring alterations in a large cohort of treatment-naive patients with advanced EGFR -mutant LUAD. source

      Not checked in the free run.

    • cites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source

      Not checked in the free run.

    • cites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROR1 binds EGFR directly, maintaining EGFR-ERBB3 heterodimers, ERBB3 phosphorylation, and PI3K-AKT pro-survival signaling.

    “which directly binds to EGFR and sustains EGFR–ERBB3 heterodimerization, ERBB3 phosphorylation and pro-survival PI3K–AKT signaling”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [126] Maeda, Y. et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J. Clin. Invest. 122, 4388–4400 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alterations in other regulators of G1/S cell cycle transition including amplification of CDK4, CDK6 and CCNE1 are prevalent and appear to be enriched in tumors that express the EGFRT790M gatekeeper mutation that confers TKI resistance, although data regarding their preferential occurrence in EGFR-mutant compared to EGFR wild-type LUAD are less consistent between studies.

    “Alterations in other regulators of G1/S cell cycle transition including amplification of CDK4, CDK6 and CCNE1 are prevalent and appear to be enriched in tumors that express the EGFRT790M gatekeeper mutation that confers TKI resistance, although data regarding their preferential occurrence in EGFR-mutant compared to EGFR wild-type LUAD are less consistent between studies73.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017). This article examines the clinical impact of co-occurring alterations in a large cohort of patients with EGFR -mutant LUAD and available circulating tumour DNA-based molecular profiling. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ROR1 also binds and phosphorylates SRC, offering an alternative route to AKT activation.

    “ROR1 can interact with and phosphorylate SRC, providing a parallel pathway to AKT activation126.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Maeda, Y. et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J. Clin. Invest. 122, 4388–4400 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In this model, Lkb1 loss changes the cytokine environment, raising IL-1β, IL-6, CXCL7, and G-CSF, which promote myeloid cell recruitment.

    “Lkb1 loss in this model results in altered tumor cytokine milieu with increased expression of interleukin 1β (IL-1β), IL-6, CXCL7 and G-CSF that foster myeloid cell recruitment135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Cristescu, R. et al. Pan-tumour genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This inflamed state is partly explained by p53 loss activating NF-κB and by greater tolerance of mutation burden, which may raise immunogenicity through neoantigens.

    “This is at least in part due to activation of the nuclear factor κB (NF-κB) pathway driven by p53 loss, as well as increased tolerance of a higher mutational burden that may ostensibly result in enhanced immunogenicity due to increased neoantigen load143, 144, 145, 146.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [143] Olagnier, D. et al. Nrf2 negatively regulates STING indicating a link between antiviral sensing and metabolic reprogramming. Nat. Commun. 9, 3506 (2018). source

      Not checked in the free run.

    • cites [144] Petitjean, A. et al. Impact of mutant p53 functional properties on TP53 mutation patterns and tumour phenotype: lessons from recent developments in the IARC TP53 database. Hum. Mutat. 28, 622–629 (2007). source

      Not checked in the free run.

    • cites [145] Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumour mutational burden. Genome Med. 9, 34 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LKB1 inactivation also affects non-immune parts of the KrasG12D mouse tumor microenvironment, raising collagen deposition via higher LOX expression and altering angiogenesis.

    “LKB1 inactivation has also been reported to impinge on non-immune components of the microenvironment of KrasG12D-mutant mouse tumors, including increased collagen deposition as a result of elevated lysyl oxidase (LOX) expression and effects on angiogenesis139, 140.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [139] Kortlever, R. M. et al. Myc cooperates with ras by programming inflammation and immune suppression. Cell 171, 1301–1315.e14 (2017). source

      Not checked in the free run.

    • cites [140] Gao, Y. et al. LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc. Natl Acad. Sci. USA 107, 18892–18897 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the KrasLSL-G12D/+; Lkb1Fl/Fl GEMM, Lkb1 ablation by Cre causes tumor-associated neutrophils to accumulate; these neutrophils suppress T cells and express more ARG1 and IL-10.

    “These findings are recapitulated in the KrasLSL-G12D/+; Lkb1Fl/Fl GEMM, where Cre-mediated Lkb1 ablation triggers marked influx of tumor-associated neutrophils with T cell suppressive properties including increased expression of Arginase 1 (ARG1) and Interleukin 10 (IL-10)135.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [135] Cristescu, R. et al. Pan-tumour genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In LKB1-deficient cells, greater EZH2 and DNMT1 methyltransferase activity silences STING; this is partly because glucose is diverted to serine biosynthesis, raising SAM.

    “Silencing of STING in this context is triggered by enhanced activity of the EZH2 and DNMT1 methyltransferases due – at least in part- to increased production of SAM through diversion of glucose towards the serine biosynthetic pathway in LKB1-deficient cells87, 136.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [87] Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumourigenesis. Nature 539, 390–395 (2016). source

      Not checked in the free run.

    • cites [136] Koyama, S. et al. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumour microenvironment. Cancer Res. 76, 999–1008 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Co-occurring alterations may be strong biomarkers of treatment response, and in many contexts more precise than single-gene markers.

    “Thus, co-occurring alterations can function as robust, and in many settings more precise, biomarkers of therapeutic response than single-gene predictors.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    KL cells depend more on nucleotide synthesis, particularly dTTP, which explains their selective sensitivity to DTYMK depletion.

    “Enhanced dependence on nucleotide (and especially dTTP) synthesis further underpins the selective sensitivity of KL cells to deoxythymidylate kinase (DTYMK) depletion”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Inge, L. J. et al. LKB1 inactivation sensitizes non-small-cell lung cancer to pharmacological aggravation of ER stress. Cancer Lett. 352, 187–195 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Certain vulnerabilities follow LKB1 inactivation regardless of KRAS status, whereas others, including dependence on lysosomal degradation, appear unique to the KL genotype.

    “While some of these vulnerabilities are associated with LKB1 inactivation irrespective of concurrent KRAS mutations, others, such as addiction to lysosomal enzymatic degradation, appear to be specific to the KL oncogenotype and thus represent de facto co-mutation-dependent vulnerabilities.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    These cells use glutaminolysis to replenish TCA cycle intermediates and respond selectively to glutaminase blockade in cell-line and mouse models.

    “rely on glutaminolysis for TCA cycle anaplerosis; thus, they are selectively sensitive to glutaminase inhibition in both cell line and mouse models92.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [92] Babur, O. et al. Systematic identification of cancer driving signalling pathways based on mutual exclusivity of genomic alterations. Genome Biol. 16, 45 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Co-occurring alterations may influence how likely and how long a targeted therapy works, and also shape how resistance arises.

    “therefore co-occurring alterations can affect not only the likelihood and duration of response to targeted therapy but also impact mechanisms of acquired resistance117.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Jakobsen, J. N., Santoni-Rugiu, E., Grauslund, M., Melchior, L. & Sorensen, J. B. Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment. Oncotarget 9, 26195–26208 (2018). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    In KRAS-mutant LUAD, KEAP1 co-mutations predict markedly poorer outcomes after platinum-doublet chemotherapy.

    “significantly worse clinical outcomes with platinum-doublet chemotherapy in KRAS-mutant LUAD99”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Jeon, S. M., Chandel, N. S. & Hay, N. AMPK regulates NADPH homeostasis to promote tumour cell survival during energy stress. Nature 485, 661–665 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Classical activating RAS pathway mutations tend to be mutually exclusive, yet atypical weakly activating mutations can cooperate oncogenically.

    “Notably, despite apparent mutual exclusivity between classical activating mutations in RAS pathway genes, oncogenic co-operativity has been observed between atypical, weakly activating mutations170.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [170] Torok, J. A. et al. Deletion of ATM in tumour but not endothelial cells improves radiation response in a primary mouse model of lung adenocarcinoma. Cancer Res. 79, 773–782 (2019). source

      Not checked in the free run.

  • The quote only partly states this claim.

    Premisecitation

    Preliminary data link KEAP1 co-mutations to poorer outcomes from pemetrexed-carboplatin or cisplatin plus pembrolizumab in non-squamous NSCLC.

    “or, as shown in preliminary data, with chemo-immunotherapy using pemetrexed-carboplatin (or cisplatin) plus the PD-1 antibody pembrolizumab in non-squamous NSCLC167.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [167] Krall, E. B. et al. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Elife 6, e33173 (2017).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    BRAF-mutant NSCLC shows elevated tumor-cell PD-L1 and responds better to PD-1/PD-L1 inhibitors.

    “BRAF-mutant NSCLCs, which are characterized by high tumor cell PD-L1 expression and more favorable clinical response to PD-1 and PD-L1 inhibitors147, 148.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [147] Meylan, E. et al. Requirement for NF-κB signalling in a mouse model of lung adenocarcinoma. Nature 462, 104–107 (2009). source

      Not checked in the free run.

    • cites [148] Dudnik, E. et al. BRAF mutant lung cancer: programmed death ligand 1 expression, tumour mutational burden, microsatellite instability status, and response to immune check-point inhibitors. J. Thorac. Oncol. 13, 1128–1137 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    BRAF, CDKN2A, CDKN2B, and FGFR3 co-alterations and MET/EGFR amplification are more common in tumors with acquired EGFR TKI resistance than before treatment, suggesting they help mediate resistance.

    “Co-alterations in BRAF, CDKN2A, CDKN2B, fibroblast growth factor receptor 3 (FGFR3) and amplification of MET and EGFR itself were all enriched in patients with acquired resistance to EGFR TKIs compared to pre-treatment tumors, indicating roles in mediating the drug resistant phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Inputs from several co-altered RAS pathway genes together reach oncogenic activity thresholds needed for transformation and tumor upkeep, while also creating treatment vulnerabilities.

    “In this setting signaling inputs from multiple co-altered RAS pathway genes coordinately contribute towards thresholds of oncogenic activity that are critical for transformation and tumor maintenance but also bestow therapeutic vulnerabilities”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The prevailing model based on one oncogenic driver does not fully account for NSCLC's clinical complexity and needs revision.

    “there is growing appreciation that the current single oncogenic driver model fails to adequately capture the clinical complexity of NSCLC and warrants revision.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Compared with KL tumors, KRAS-mutant tumors that also carry TP53 co-mutations show high response rates to PD-1 axis immunotherapy and much better PFS and OS.

    “KRAS-mutant tumors bearing co-mutations in TP53 exhibit high rates of clinical response to PD-1 axis immunotherapy and markedly improved progression-free and overall survival compared to KL68.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Skoulidis, F. et al. STK11/LKB1 mutations and PD-1 inhibitor resistance in KRAS-mutant lung adenocarcinoma. Cancer Discov. 8, 822–835 (2018). This study identifies inactivating LKB1 genomic alterations as a major driver of de novo resistance to PD-1 axis blockade in KRAS -mutant LUAD. source

      Not checked in the free run.

66 of 66

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • KRAS mutations account for about 78% of RAS mutations in NSCLC, and activating missense KRAS mutations occur in about 25% of NSCLCs, usually mutually exclusive with other actionable drivers such as EGFR, BRAF and ALK.

    “KRAS mutations predominate in NSCLCs, accounting for ~78% of all RAS mutations found in such tumours17. The activating missense KRAS mutations that occur in ~25% of NSCLCs19–23 are typically mutually exclusive with other clinically actionable driver mutations, such as those in EGFR, BRAF and ALK24.”

    From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [19]

  • Co-occurrence of mutant KRAS and LKB1 deficiency in lung cancer patients results in more aggressive tumors, higher metastasis frequency, and therapy resistance.

    “Co-occurrence of mutant KRAS and LKB1 deficiency in patients with lung cancer resulted in more aggressive tumors, higher frequency of metastasis, and therapy resistance67.”

    From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [67]

Cites

Flagged first, then by citations

2 of the 195 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
Skoulidis, F., & Heymach, J. V.
Affiliations
The University of Texas MD Anderson Cancer Center (US)
Corresponding author
Skoulidis, Ferdinandos
ORCID
Venue
Nature Reviews Cancer
Publisher
Springer Science and Business Media LLC
Published
2019-08-12
Volume
19
Issue
9
Pages
495-509
ISSN
  • 1474-175X (ISSN-L)
  • 1474-1768
DOI
10.1038/s41568-019-0179-8
PMC
PMC7043073
OpenAlex
W2967210753
Cited by
1,019
References
195
Citations by year
2026: 132 · 2025: 143 · 2024: 162 · 2023: 168 · 2022: 181 · 2021: 159 · 2020: 70 · 2019: 3
FWCI
17.55
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature reviews. Cancer (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health (5r01ca205150-04)
  • National Cancer Institute (R01-CA205150, P50CA070907, P30CA016672)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
non-small cell lung cancer, TP53 mutation, STK11/LKB1, EGFR mutation, ALK rearrangement, ROS1 rearrangement, RET fusion, receptor tyrosine kinase inhibitors, tumor suppressor, tumor microenvironment, tumor heterogeneity, precision immunotherapy, therapeutic vulnerabilities
MeSH terms
Proto-Oncogene Mas, AMP-Activated Protein Kinase Kinases, Algorithms, Animals, Carcinoma, Non-Small-Cell Lung, Humans, Immunotherapy, Lung Neoplasms, Mutation, Oncogenes, Phenotype, Prognosis, Genome, Human, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, Disease-Free Survival, Mice, ErbB Receptors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review