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

In the paper

“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.”

What the sources say

• Partly supported

  The Results report resistance to first-, second-, and third-generation EGFR TKIs for six tested exon 20 insertions, but explicitly except EGFR A763insFQEA; the claim's assertion that all such mutants resist all approved TKIs is therefore too broad. The steric-hindrance Results section and Discussion support the proposed mechanism and poziotinib activity in vitro and in vivo. Page numbers are not available in the supplied passages. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says EGFR exon 20 insertions are typically unresponsive to first- and second-generation EGFR TKIs, while the Discussion describes steric changes and reports preclinical and clinical activity for poziotinib (pages unavailable). But the paper identifies an insertion sensitive to those approved TKIs, so the claim that all such mutants resist all approved EGFR TKIs is too absolute. It also does not explicitly establish poziotinib sensitivity in both in vitro and in vivo models. (LLM, conf=0.89)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• ?Could not verify

  The paper’s discussion of LKB1 mutations in non-small cell lung carcinoma and its findings on AMPK-dependent redox regulation (section labeled Abstract; page unavailable) do not address KEAP1-mutant NSCLC. Searches for KEAP1, detoxification pathways, and clinical prognosis found no passage supporting the claimed aggressive phenotype or independent negative prognostic status. (LLM, conf=0.76)

  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). sourceExperimental — accuracy not yet measured

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Partly supported

  The Somatically acquired DNA alterations section reports PIK3CA, TP53 and RB1 mutations, and NKX2-1 amplification, in lung adenocarcinoma. It does not compare their frequencies between early- and advanced-stage tumours. The Description of aberrant RNA transcripts section discusses CTNNB1 alternative splicing, not a stage-specific mutation frequency; the claimed stage comparisons are therefore unsupported by this copy. (LLM, conf=0.84)

  cites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (page unavailable) report PIK3CA and CTNNB1 mutations and TP53 and RB1 mutations, along with NKX2.1 amplification, in EGFR-mutant tumors before treatment. The paper does not compare early- and advanced-stage LUADs, so it does not establish either the claimed higher frequencies of PIK3CA and CTNNB1 or comparable frequencies of the other alterations across stages. (LLM, conf=0.82)

  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. sourceExperimental — accuracy not yet measured
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• ?Could not verify

  The Results and Discussion passages describe angiogenesis and vascular remodeling in KRasG12D mouse lung tumors following Myc activation, not LKB1 inactivation. A search of our copy for LKB1, LOX, and collagen deposition found no passage addressing the claimed LKB1–LOX–collagen mechanism; the angiogenesis findings therefore do not verify the claim attributed to this source. The supplied passages have no page numbers. (LLM, conf=0.77)

  cites [139] Kortlever, R. M. et al. Myc cooperates with ras by programming inflammation and immune suppression. Cell 171, 1301–1315.e14 (2017). sourceExperimental — accuracy not yet measured
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [64] Campbell, P. J. Cliques and schisms of cancer genes. Cancer Cell 32, 129–130 (2017). source

In the paper

“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.”

What the sources say

• Not checked yetcites [16] Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009). source
• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [34] Cancer Genome Atlas Research, N. Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543–550 (2014). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [95] DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumourigenesis. Nature 475, 106–109 (2011). source
• Not checked yetcites [96] DeNicola, G. M. et al. NRF2 regulates serine biosynthesis in non-small-cell lung cancer. Nat. Genet. 47, 1475–1481 (2015). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [80] Marty, R. et al. MHC-I genotype restricts the oncogenic mutational landscape. Cell 171, 1272–1283 (2017). e15. source

In the paper

“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.”

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [84] Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007). source
• Not checked yetcites [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 yetcites [86] Zhang, H. et al. Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb repressive complex 2. Nat. Commun. 8, 14922 (2017).

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [84] Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007). source

In the paper

“Somatic mutations in LKB1 and KEAP1 significantly co-occur with mutant KRAS and with each other in NSCLC15, 59, 63, 91.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [75] Ortmann, C. A. et al. Effect of mutation order on myeloproliferative neoplasms. N. Engl. J. Med. 372, 601–612 (2015). source
• Not checked yetcites [76] Swanton, C. Cancer evolution constrained by mutation order. N. Engl. J. Med. 372, 661–663 (2015). source

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [101] Feldser, D. M. et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature 468, 572–575 (2010). source
• Not checked yetcites [102] Junttila, M. R. et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature 468, 567–571 (2010). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [122] Malladi, S. et al. Metastatic latency and immune evasion through autocrine inhibition of WNT. Cell 165, 45–60 (2016). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [103] Muzumdar, M. D. et al. Clonal dynamics following p53 loss of heterozygosity in Kras-driven cancers. Nat. Commun. 7, 12685 (2016). source

In the paper

“which directly binds to EGFR and sustains EGFR–ERBB3 heterodimerization, ERBB3 phosphorylation and pro-survival PI3K–AKT signaling”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“ROR1 can interact with and phosphorylate SRC, providing a parallel pathway to AKT activation126.”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [135] Cristescu, R. et al. Pan-tumour genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018). source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [135] Cristescu, R. et al. Pan-tumour genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018). source

In the paper

“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.”

What the sources say

• Not checked yetcites [87] Kottakis, F. et al. LKB1 loss links serine metabolism to DNA methylation and tumourigenesis. Nature 539, 390–395 (2016). source
• Not checked yetcites [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

In the paper

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

In the paper

“Enhanced dependence on nucleotide (and especially dTTP) synthesis further underpins the selective sensitivity of KL cells to deoxythymidylate kinase (DTYMK) depletion”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

In the paper

“rely on glutaminolysis for TCA cycle anaplerosis; thus, they are selectively sensitive to glutaminase inhibition in both cell line and mouse models92.”

What the sources say

• Not checked yetcites [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

In the paper

“therefore co-occurring alterations can affect not only the likelihood and duration of response to targeted therapy but also impact mechanisms of acquired resistance117.”

What the sources say

• Not checked yetcites [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

In the paper

“significantly worse clinical outcomes with platinum-doublet chemotherapy in KRAS-mutant LUAD99”

What the sources say

• Not checked yetcites [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

In the paper

“Notably, despite apparent mutual exclusivity between classical activating mutations in RAS pathway genes, oncogenic co-operativity has been observed between atypical, weakly activating mutations170.”

What the sources say

• Not checked yetcites [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

In the paper

“or, as shown in preliminary data, with chemo-immunotherapy using pemetrexed-carboplatin (or cisplatin) plus the PD-1 antibody pembrolizumab in non-squamous NSCLC167.”

What the sources say

• Not checked yetcites [167] Krall, E. B. et al. KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Elife 6, e33173 (2017).

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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.”

In the paper

“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”

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [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