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A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response
Open accessAbstract
Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.
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“LKB1 deficiency by immunohistochemistry is associated with lack of benefit from the addition of the vascular endothelial growth factor A (VEGFA) inhibitor bevacizumab to platinum doublet chemotherapy163, 164.”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [164]
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NF1 Deletion Generates Multiple Subtypes of Soft-Tissue Sarcoma That Respond to MEK Inhibition
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“This heterogeneity is a salient feature of primary tumor systems (46, 47) that permit modeling of diverse biology andmay reflect differences in additional acquired somatic mutations and/or the influence of the complex microenvironment.”
BackgroundA review on epidermal growth factor receptor's role in breast and non-small cell lung cancer
Subramaniyan, V., Fuloria, S., Gupta, G., Kumar, D. H., Sekar, M., Sathasivam, K. V., Sudhakar, K., Alharbi, K. S., Almalki, W. H., Afzal, O., et al. (2021) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2021.109735 · Cited by 86
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Patient‑derived xenograft mouse models: A high fidelity tool for individualized medicine (Review)
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“Furthermore, coclinical trials may also verify relevant hypotheses in a clinical setting and thereby affect the design of future clinical studies (57).”
BackgroundSelf-citationQuantitative preclinical PET imaging: opportunities and challenges
Kuntner, C., & Stout, D. (2014) · Frontiers in Physics · doi:10.3389/fphy.2014.00012 · Cited by 84
“This avatar approach is a promising concept and has been shown in a murine lung cancer study that mirrored an ongoing human clinical trial in patients with KRAS-mutant lung cancers [120].”
ResultClinical and Molecular Characteristics of NF1 -Mutant Lung Cancer
Redig, A. J., Capelletti, M., Dahlberg, S. E., Sholl, L. M., Mach, S. L., Fontes, C., Shi, Y., Chalasani, P., & Janne, P. A. (2016) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-2377 · Cited by 84
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Optimizing biologically targeted clinical trials for neurofibromatosis
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“This bi-directional feedback facilitates the development of translatable outcomes as well as provides a forum to cross-inform each group, similar to the co-clinical trial infrastructures operational for other cancer types [85,86].”
Targeted therapies in development for non-small cell lung cancer
Dy, G. K., & Reungwetwattana, T. (2013) · Journal of Carcinogenesis · doi:10.4103/1477-3163.123972 · Cited by 80
“[171,28] Similarly, the addition of selumetinib, a MEK inhibitor, markedly improved the response of KRAS mutant tumors to docetaxel.[172] However, the concurrent loss of LKB1 (also known as STK11), a tumor suppressor gene, abrogated the synergistic effect of the combination of docetaxel with selumetinib in a KRAS muta…”
BackgroundmTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma
Giovannini, M., Bonne, N.-X., Vitte, J., Chareyre, F., Tanaka, K., Adams, R., Fisher, L. M., Valeyrie‐Allanore, L., Wolkenstein, P., Goutagny, S., et al. (2014) · Neuro-Oncology · doi:10.1093/neuonc/not242 · Cited by 81
“Rapamycin treatment was dosed 8 mg/kg/ day and administered by intraperitoneal injection following a schedule of once a day, 5 of 7 days for the ESC-FC1801 xenografts (14 d treatment), 08031-9 syngrafts (36 d treatment followed by 14 d withdrawal for 3 mice), and P0-SCH-D(39-121)-27 transgenic mice during the first 2…”
BackgroundMethodInfluentialAlkema, N. G., Wisman, G. B. A., van der Zee, A. G. J., van Vugt, M. A. T. M., & de Jong, S. (2015) · Drug Resistance Updates · doi:10.1016/j.drup.2015.11.005 · Cited by 84
“Indeed, GEMMs are being implemented in so-called co-clinical trials for other cancer types, like lung cancer, aiming to identify drug responses and uncover resistance mechanisms as observed in the clinic (Chen et al., 2012; Nardella et al., 2011).”
BackgroundJanne, P. A., Smith, I. C. P., McWalter, G., Mann, H., Dougherty, B. A., Walker, J., Orr, M. C. M., Hodgson, D., Shaw, A. T., Pereira, J. R., et al. (2015) · British Journal of Cancer · doi:10.1038/bjc.2015.215 · Cited by 77
“www.bjcancer.com | DOI:10.1038/bjc.2015.215 201 determined whether results were confounded by other oncogenic aberrations, such as mutations in TP53 and LKB1 (Chen et al, 2012; Sherwood et al, 2014).”
BackgroundInfluentialChoi, H., Deng, J., Li, S., Silk, T., Dong, L., Brea, E. J., Houghton, S., Redmond, D., Zhong, H., Boiarsky, J., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.03.066 · Cited by 72
“Overall tumor volumes within the whole lung were quantified using 3D slicer software to reconstruct MRI volumetric measurements as previously described (Chen et al., 2012).”
BackgroundMethodOvercoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS
Kitajima, S., Asahina, H., Chen, T., Guo, S., Quiceno, L. G., Cavanaugh, J. D., Merlino, A. A., Tange, S., Terai, H., Kim, J. W., et al. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.08.009 · Cited by 75
“Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs.”
InfluentialSelf-citationBange, E., Marmarelis, M. E., Hwang, W.-T., Yang, Y.-X., Thompson, J. C., Rosenbaum, J., Bauml, J. M., Ciunci, C., Alley, E. W., Cohen, R. B., et al. (2019) · JCO Precision Oncology · doi:10.1200/po.18.00326 · Cited by 74
“In KRASmutant mice, co-mutation with STK11 was associated with resistance to anticancer therapy, whereas co-mutation with TP53 was not.(8) In humans, STK11 mutation alone does not appear to be predictive of response to chemotherapy, whereas KRAS/STK11 co-mutation has been associated with worse PFS after chemotherapy.”
BackgroundHata, A. N., Yeo, A., Faber, A. C., Lifshits, E., Chen, Z., Cheng, K. A., Walton, Z., Sarosiek, K. A., Letai, A., Heist, R. S., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3728 · Cited by 74
“Tumor burden was quantified by serial MRI scanning as described (23).”
Self-citationLan, B., Ma, C., Zhang, C., Chai, S., Wang, P., Ding, L., & Wang, K. (2018) · Oncotarget · doi:10.18632/oncotarget.23969 · Cited by 76
“Co-mutation of STK11/LKB1 and KRAS was shown to downregulate PD-L1 expression level in NSCLC cell lines; in contrast, co-mutation of tp53 and KRAS was shown an upregulating effect [20, 21].”
BackgroundMEK inhibition in non-small cell lung cancer
Stinchcombe, T. E., & Johnson, G. L. (2014) · Lung Cancer · doi:10.1016/j.lungcan.2014.09.005 · Cited by 69
Biomarkers in Lung Adenocarcinoma: A Decade of Progress
Sholl, L. M. (2014) · Archives of Pathology & Laboratory Medicine · doi:10.5858/arpa.2014-0128-ra · Cited by 75
“Interestingly, the mice with combined KRAS and TP53 mutations benefitted from selumetinib and docetaxel, but those with KRAS þ LKB1 mutations did not.(69) In the absence of a next-generation sequencing approach, comprehensive TP53 mutation and deletion analysis is challenging owing to the breadth of possible alteratio…”
BackgroundPeng, D. H., Rodriguez, B. L., Diao, L., Gaudreau, P.-O., Padhye, A., Konen, J. M., Ochieng, J. K., Class, C. A., Fradette, J. J., Gibson, L., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22875-w · Cited by 72
Reactive metabolite production is a targetable liability of glycolytic metabolism in lung cancer
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Colen, R. R., Foster, I. T., Gatenby, R. A., Giger, M. L., Gillies, R. J., Gutman, D. A., Heller, M. T., Jain, R., Madabhushi, A., Madhavan, S., et al. (2014) · Translational Oncology · doi:10.1016/j.tranon.2014.07.007 · Cited by 72
“This newer approach to integrated cross-species testing, termed coclinical trials, involves concurrent assessment of novel drug combinations in mouse and human-in-mouse models of tumors, and in patients with recurrent or metastatic disease with whom the mice are genotypically matched [52,53].”
BackgroundPreclinical Modeling of KIF5B–RET Fusion Lung Adenocarcinoma
Huang, Q., Schneeberger, V. E., Luetteke, N., Jin, C., Afzal, R., Budzevich, M. M., Makanji, R. J., Martinez, G. V., Shen, T., Zhao, L., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0258 · Cited by 72
“The immune competent C/KR mouse model that we developed here provides a resource allowing the direct side-byside comparison of two drugs in preclinical studies or co-clinical trials (34, 35) of RET fusion–associated lung adenocarcinoma.”
MethodHan, J. H., Kim, Y. K., Kim, H., Lee, J., Oh, M. J., Kim, M., Kim, K. H., Kim, K. H., Yoon, H. J., Lee, M., et al. (2022) · 癌症：英文版 · doi:10.1002/cac2.12332 · Cited by 73
“Accumulating evidence suggests that co-mutation of LKB1 in KRAS-mutated cancers confers therapeutic resistance [8, 27, 28].”
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Atm deletion with dual recombinase technology preferentially radiosensitizes tumor endothelium
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Self-citationBai, X., Guo, Z.-Q., Zhang, Y.-P., Fan, Z., Liu, L., Liu, L., Long, L.-L., Ma, S.-C., Wang, J., Fang, Y., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36892-4 · Cited by 72
Assessing Therapeutic Efficacy of MEK Inhibition in a KRASG12C-Driven Mouse Model of Lung Cancer
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“These co-occurring genomic changes could also lead to different therapeutic responses andmay render KRAS-mutant tumors even more chemoresistant (11, 12).”
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Lung cancer deficient in the tumor suppressor GATA4 is sensitive to TGFBR1 inhibition
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Establishing the Impact of Vascular Damage on Tumor Response to High-Dose Radiation Therapy
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In Vitro and In Vivo Models for Analysis of Resistance to Anticancer Molecular Therapies
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“Very recently, sophisticated GEMM models of lung cancer were used to evaluate responsiveness to combined therapy of docetaxel and the MEK inhibitor selumetinib (AZD6244), according to a co-clinical trial effort [45].”
Ricciuti, B., Leonardi, G. C., Metro, G., Grignani, F., Paglialunga, L., Bellezza, G., Baglivo, S., Mencaroni, C., Baldi, A., Zicari, D., et al. (2015) · Expert Review of Respiratory Medicine · doi:10.1586/17476348.2016.1115349 · Cited by 65
“Importantly, the addition of selumetinib provided significant benefit for mice with lung cancer caused by KRAS and TP53 mutations, whereas mice harboring KRAS and LKB1mutations showed primary resistance to this combination therapy.[95] Of note, preclinical data indicate that MEK inhibitors cause inhibition of cell pro…”
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“Co-clinical trials in engineered mouse models have demonstrated that the loss of TP53 or STK11 impaired the response of KRAS-mutant cancers to docetaxel monotherapy and that the addition of selumetinib provided substantial benefit for mice with lung cancers caused by KRAS and KRAS/TP53 mutations [31].”
Modeling Targeted Inhibition of MEK and PI3 Kinase in Human Pancreatic Cancer
Junttila, M. R., Devasthali, V., Cheng, J. H., Castillo, J., Metcalfe, C., Clermont, A. C., Otter, D. D., Chan, E., Bou-Reslan, H., Cao, T. C., et al. (2014) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-14-0030 · Cited by 61
“MAPK pathway inhibition alone and in combination with chemotherapy showed promising efficacy in a mutant Kras-driven genetically engineered mouse model (GEMM) of non–small cell lung carcinoma (NSCLC) and translated into a positive clinical outcome (6, 7).”
BackgroundMethodInfluentialTargeting the LKB1 Tumor Suppressor
Zhao, R., & Xu, Z. (2014) · Current Drug Targets · doi:10.2174/1389450114666140106095811 · Cited by 64
Tumor-Targeted Synergistic Blockade of MAPK and PI3K from a Layer-by-Layer Nanoparticle
Dreaden, E. C., Kong, Y. W., Morton, S. W., Correa, S., Choi, K. Y., Shopsowitz, K. E., Renggli, K., Drapkin, R., Yaffe, M. B., & Hammond, P. T. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0013 · Cited by 59
Implications of KRAS mutations in acquired resistance to treatment in NSCLC
Re, M. D., Rofi, E., Restante, G., Crucitta, S., Arrigoni, E., Fogli, S., Maïo, M. D., Petrini, I., & Danesi, R. (2017) · Oncotarget · doi:10.18632/oncotarget.23553 · Cited by 64
“In preclinical models, docetaxel in combination with selumetinib showed an important inhibition of tumor growth and regression [78].”
BackgroundNEDD9 promotes lung cancer metastasis through epithelial-mesenchymal transition
Jin, Y., Li, F., Zheng, C., Wang, Y., Fang, Z., Guo, C., Wang, X., Liu, H., Deng, L., Li, C., et al. (2013) · International Journal of Cancer · doi:10.1002/ijc.28568 · Cited by 62
Self-citationExperimental animal modeling for immuno-oncology
Li, Q., Feuer, G., Ouyang, X., & An, X. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.002 · Cited by 63
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“In particular, we have previously described a co-clinical trial using a murine model recapitulating human NSCLC driven by an activating Kras mutation (21).”
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“Tumor volume within the whole lung was quantified using 3-D slicer software to reconstruct MRI volumetric measurements, as described previously (16).”
Self-citationThe Future of Patient-Derived Tumor Xenografts in Cancer Treatment
Sia, D., Moeini, A., Labgaa, I., & Villanueva, A. (2015) · Pharmacogenomics · doi:10.2217/pgs.15.102 · Cited by 58
The mutant p53 mouse as a pre-clinical model
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Emerging Therapeutic Implications of STK11 Mutation: Case Series
Laderian, B., Mundi, P. S., Fojo, T., & Bates, S. E. (2020) · The Oncologist · doi:10.1634/theoncologist.2019-0846 · Cited by 58
“Genetically engineered mice with KRAS-, KRAS/TP53-, or KRAS/STK11-mutant adenocarcinomas of the lung were randomized to receive docetaxel by intraperitoneal injection every other day, the oral MEK inhibitor selumetinib daily, or docetaxel in combination with selumetinib [19].”
MethodInhibition of autophagy and MEK promotes ferroptosis in Lkb1-deficient Kras-driven lung tumors
Bhatt, V. D., Lan, T., Wang, W., Kong, J., Lopes, E. C., Wang, J., Khayati, K., Raju, A., Rangel, M., Lopez, E., et al. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-05592-8 · Cited by 61
“Whereas Kras-p53 mutant tumors respond to combination therapy with docetaxel and the MEK inhibitor Selumetinib, Kras-Lkb1 mutant tumors do not [12].”
BackgroundOncology Drug Discovery: Planning a Turnaround
Toniatti, C., Jones, P. S., Graham, H., Pagliara, B., & Draetta, G. F. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-13-0452 · Cited by 57
Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma
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“resistant to both standard-of-care docetaxel and combination treatment with a MEK inhibitor (7).”
Self-citationYamaguchi, N., VanderLaan, P. A., Folch, E. E., Boucher, D. H., Canepa, H. M., Kent, M. S., Gangadharan, S. P., Majid, A., Kocher, O. N., Goldstein, M. A., et al. (2013) · Lung Cancer · doi:10.1016/j.lungcan.2013.07.013 · Cited by 56
Self-citationProteasome Inhibitors Block DNA Repair and Radiosensitize Non-Small Cell Lung Cancer
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“These mutations are found in tumors that are particularly aggressive and resistant to therapy, and for which targeted therapies are unavailable [18,19].”
BackgroundMolecular diagnostics of lung cancer in the clinic
Sholl, L. M. (2017) · Translational Lung Cancer Research · doi:10.21037/tlcr.2017.08.03 · Cited by 56
“Other alterations, such as loss of SMARCA4, have been more broadly implicated as negative prognostic factors (47,48), whereas still others, such as loss function of STK11/LKB1, may predict specific therapeutic vulnerabilities among KRAS mutated tumors (49,50).”
BackgroundPredicting Drug Responsiveness in Human Cancers Using Genetically Engineered Mice
Usary, J., Zhao, W., Darr, D. B., Roberts, P. J., Liu, M., Balletta, L., Karginova, O. A., Jordan, J. L., Combest, A. J., Bridges, A. S., et al. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-13-0522 · Cited by 55
“Recently, academic and industry researchers have begun simultaneous efficacy testing at medium throughput, employing larger numbers of compounds (5-50) in larger numbers of GEMMs (100-1000) (15, 16).”
Self-citationWeisberg, E., Nonami, A., Chen, Z., Liu, F., Zhang, J., Sattler, M., Nelson, E. A., Cowens, K. B., Christie, A. L., Mitsiades, C. S., et al. (2014) · Leukemia · doi:10.1038/leu.2014.149 · Cited by 53
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ZEB1 suppression sensitizes KRAS mutant cancers to MEK inhibition by an IL17RD-dependent mechanism
Peng, D. H., Kundu, S. T., Fradette, J. J., Diao, L., Tong, P., Byers, L. A., Wang, J., Canales, J. R., Villalobos, P. A., Mino, B., et al. (2019) · Science Translational Medicine · doi:10.1126/scitranslmed.aaq1238 · Cited by 53
Image-guided radiotherapy platform using single nodule conditional lung cancer mouse models
Herter-Sprie, G. S., Korideck, H., Christensen, C. L., Herter, J. M., Rhee, K., Berbeco, R. I., Bennett, D. G., Akbay, E. A., Kozono, D., Mak, R. H., et al. (2014) · Nature Communications · doi:10.1038/ncomms6870 · Cited by 52
Self-citationMechanisms underlying18F-fluorodeoxyglucose accumulation in colorectal cancer
Kawada, K., Iwamoto, M., & Sakai, Y. (2016) · World Journal of Radiology · doi:10.4329/wjr.v8.i11.880 · Cited by 61
Varkaris, A. S., Corn, P. G., Parikh, N. U., Efstathiou, E., Song, J. H., Lee, Y.-C., Aparicio, A. M., Hoang, A. G., Gaur, S., Thorpe, L., et al. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-0235 · Cited by 52
“representation of islets: (a) live cells growing in proximity to the central vessel, (b) live cells on the periphery of the islet, (c) apoptotic and necrotic cells, (1) axial plane, (2) coronal plane showing red blood cells in center of islet.”
BackgroundKRAS mutant lung cancer: progress thus far on an elusive therapeutic target
Bhattacharya, S., Socinski, M. A., & Burns, T. F. (2015) · Clinical and Translational Medicine · doi:10.1186/s40169-015-0075-0 · Cited by 53
“These studies lead in part to the realization that responses to agents may depend on presence or/absence of genetic modifiers such as TP53 mutations, CDKN2A alterations or STK11/LKB1 alterations [17, 39].”
BackgroundGandara, D. R., Leighl, N. B., Delord, J., Barlési, F., Bennouna, J., Zalcman, G., Infante, J. R., Reckamp, K. L., Kelly, K. L., Shepherd, F. A., et al. (2016) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2016.11.2218 · Cited by 49
“In particular, combinations of MEK inhibitors with taxanes such as docetaxel have demonstrated marked enhancement of cytotoxic activity against KRAS-mutated lung cancer in vivo and in clinical trials.(25,27) Trametinib is a reversible MEK1/2 inhibitor active in cancers with RAS-RAFMEK pathway alterations.”
BackgroundSelf-citationStudying cancer metastasis: Existing models, challenges and future perspectives
van Marion, D. M. S., Domańska, U., Timmer‐Bosscha, H., & Walenkamp, A. (2015) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2015.08.009 · Cited by 48
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Adult lung stem cells and their contribution to lung tumourigenesis
Asselin-Labat, M.-L., & Filby, C. E. (2012) · Open Biology · doi:10.1098/rsob.120094 · Cited by 47
“These models have been successfully used to predict response to treatment [97], but also to study the cells of origin in lung adenocarcinoma.”
MethodToward personalized cancer nanomedicine – past, present, and future
Stegh, A. H. (2012) · Integrative Biology · doi:10.1039/c2ib20104f · Cited by 51
Targeting KRAS mutant lung cancer: light at the end of the tunnel
Drosten, M., & Barbacid, M. (2021) · Molecular Oncology · doi:10.1002/1878-0261.13168 · Cited by 49
“…Kras oncogene is sufficient to drive lung cancer in these GEM models, most relevant studies have used models that combine Kras mutations with mutations or deletion in the p53 tumor suppressor and, to a lesser extent, in LKB1/STK11, another tumor suppressor frequently inactivated in LUAD [31,32].”
BackgroundOpportunities and Challenges in the Era of Molecularly Targeted Agents and Radiation Therapy
Lin, S. H., George, T. J., Ben‐Josef, E., Bradley, J. D., Choe, K. S., Edelman, M. J., Guha, C., Krishnan, S., Lawrence, T. S., Le, Q., et al. (2013) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/djt055 · Cited by 47
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Self-citationHeightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers
Momcilovic, M., McMickle, R., Abt, E., Seki, A., Simko, S. A., Magyar, C., Stout, D. B., Fishbein, M. C., Walser, T. C., Dubinett, S. M., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-0797 · Cited by 46
“P-Erk staining was not detectable in KLluc lung tumors (data not shown), which agrees with previously published reports (29).”
Manning, H. C., Buck, J. R., & Cook, R. S. (2016) · Journal of Nuclear Medicine · doi:10.2967/jnumed.115.157917 · Cited by 46
“demonstrated in a murine lung cancer coclinical trial that the concomitant loss of either of 2 clinically relevant tumor suppressors (p53 or Lkb1) markedly impaired the response of Kras mutant cancers to docetaxel monotherapy (46).”
BackgroundLKB1 Deficiency Renders NSCLC Cells Sensitive to ERK Inhibitors
Caiola, E., Iezzi, A., Tomanelli, M., Bonaldi, E., Scagliotti, A., Colombo, M., Guffanti, F., Micotti, E., Garassino, M. C., Minoli, L., et al. (2019) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2019.10.009 · Cited by 45
“It has been reported that the KRAS/LKB1 double mutation in murine lung tumors promotes tumor burden, invasion, and metastasis.(28,29) Our data suggest that ERK inhibition could also be effective in tumors harboring KRAS/LKB1 double mutation, thus increasing the therapeutic strategies for this prognostically unfavorabl…”
BackgroundTang, Z., Hu, J. S., Li, X.-C., Wang, W. J., Zhang, H.-Y., Guo, Y., Shuai, X., Chu, Q., Xie, C., Lin, D., et al. (2024) · Developmental Cell · doi:10.1016/j.devcel.2024.10.010 · Cited by 46
Zhu, J., Wang, M., Zhu, M., He, J., Wang, J.-C., Li, J., Wang, X. F., Xiang, J.-Q., & Wei, Q. (2015) · Scientific Reports · doi:10.1038/srep08250 · Cited by 45
Self-citationProgrammable Molecular Scissors: Applications of a New Tool for Genome Editing in Biotech
Saha, S. K., Saikot, F. K., Rahman, M. S., Jamal, M. A. H. M., Rahman, S. M. K., Islam, S. M. R., & Kim, K. (2018) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2018.11.016 · Cited by 48
“Moreover, these models can be used to screen anticancer agents and identify drug-resistance mechanisms (Figure 6).(204,205) Genomeediting technology based on CRISPR allows us to generate large stockpiles of ESC lines with numerous arrangements of basic or restrictive mutations in oncogenes and tumor suppressor genes.”
BackgroundInoue, A., Deem, A. K., Kopetz, S., Heffernan, T. P., Draetta, G. F., & Carugo, A. (2019) · Cancers · doi:10.3390/cancers11091321 · Cited by 46
Selective anti-cancer agents as anti-aging drugs
Blagosklonny, M. V. (2013) · Cancer Biology & Therapy · doi:10.4161/cbt.27350 · Cited by 43
“Numerous agents targeting mTOR, PI-3K, growth factor receptors, and related tyrosine kinases, Ras, Raf, and B-Raf, S6K, MEK1/2 have been tested to treat cancer.(73-86) The mTOR pathway is almost obligatorily activated in cancer.”
BackgroundTreating KRAS -mutant NSCLC: latest evidence and clinical consequences
Garrido, P., Olmedo, M. E., Gómez, A., Ares, L. P., López‐Ríos, F., Rosa-Rosa, J. M., & Palacios, J. (2017) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834017719829 · Cited by 45
Selumetinib for the treatment of cancer
Ciombor, K. K., & Bekaii‐Saab, T. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2015.982275 · Cited by 42
“This particular combination was selected on the basis of preclinical data showing greater tumor growth inhibition or regression and apoptosis, as well as synergism, between docetaxel and selumetinib in in vivo models [8,25,50].”
BackgroundCaiola, E., Falcetta, F., Giordano, S., Marabese, M., Garassino, M. C., Broggini, M., Pastorelli, R., & Brunelli, L. (2018) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-018-0954-5 · Cited by 41
Venugopalan, A., Lee, M.-J., Niu, G., Medina-Echeverz, J., Tomita, Y., Lizak, M. J., Cultraro, C. M., Simpson, R. M., Chen, X., Trepel, J. B., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11021 · Cited by 40
“These immediate-early treatment responses of tumors may be measured by 18F-fluoro-2-deoxy-glucose positron emission tomography (FDG-PET), a very sensitive and clinically relevant approach [22, 23].”
BackgroundGao, Y., Päivinen, P., Tripathi, S., Domènech-Moreno, E., Wong, I. P. L., Vaahtomeri, K., Nagaraj, A. S., Talwelkar, S. S., Foretz, M., Verschuren, E. W., et al. (2022) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-2049 · Cited by 40
“Importantly, the presence of LKB1 mutations or reduction of LKB1 expression in patients with lung cancer associates with a more aggressive clinical phenotype (2) and resistance to conventional chemotherapy (3) as well as target therapies inhibiting either downstream effectors of KRAS signaling (4), suggesting novel th…”
BackgroundModulation of Bax and mTOR for Cancer Therapeutics
Li, R., Ding, C., Zhang, J., Xie, M., Park, D., Ding, Y., Chen, G., Zhang, G., Gilbert‐Ross, M., Zhou, W., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-2356 · Cited by 40
“It has been previously reported that pAKT is upregulated in lung tumor tissues from KL mice (34).”
BackgroundSelf-citationDistribution of KRAS, DDR2, and TP53 gene mutations in lung cancer: An analysis of Iranian patients
Fathi, Z., Mousavi, S. A., Roudi, R., & Ghazi, F. (2018) · PLoS ONE · doi:10.1371/journal.pone.0200633 · Cited by 41
KRAS G12C-mutant driven non-small cell lung cancer (NSCLC)
Rosell, R., Codony‐Servat, J., González, J., Santarpía, M., Jain, A. S., Shivamallu, C., Wang, Y., Giménez-Capitán, A. A., Molina‐Vila, M. Á., Nilsson, J. A., et al. (2023) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2023.104228 · Cited by 42
Self-citationTargeting Pathways Downstream of KRAS in Lung Adenocarcinoma
Zhu, Z., Golay, H. G., & Barbie, D. A. (2014) · Pharmacogenomics · doi:10.2217/pgs.14.108 · Cited by 40
Wu, Q., Li, J., Sun, S., Chen, X., Zhang, H., Li, B., & Sun, S. (2017) · Bioscience Reports · doi:10.1042/bsr20171072 · Cited by 38
Self-citationAnti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy
Johnson, L., Huseni, M. A., Smyczek, T., Lima, A., Yeung, S., Cheng, J. H., Molina, R., Kan, D., Mazière, A. M. G. L. D., Klumperman, J., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci67892 · Cited by 38
“Moreover, GEMMs have been newly leveraged to conduct “coclinical” trials that are designed to mirror ongoing human clinical trials and identify predictive genetic and PD biomarkers that can be validated by interrogating patient samples collected from the concurrent human clinical trials (30).”
Imaging Proteolytic Activity in Live Cells and Animal Models
Galban, S., Jeon, Y., Bowman, B. M., Stevenson, J., Sebolt, K. A., Sharkey, L., Lafferty, M., Hoff, B., Butler, B., Wigdal, S. S., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0066248 · Cited by 44
“Genetically engineered mouse models recapitulating a variety of human cancers are commonly used in the evaluation of therapeutics as co-clinical trials [17,18].”
BackgroundA co-clinical platform to accelerate cancer treatment optimization
Lunardi, A., & Pandolfi, P. P. (2014) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2014.10.008 · Cited by 38
Self-citationLeong, T. L., Marini, K. D., Rossello, F. J., Jayasekara, S. N., Russell, P. A., Prodanovic, Z., Kumar, B., Ganju, V., Alamgeer, M., Irving, L. B., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0106862 · Cited by 38
“In addition, ‘‘co-clinical’’ trials are now possible, where patient and mouse receive the same therapy [8].”
BackgroundKu, B. M., Bae, Y.-H., Koh, J., Sun, J., Lee, S., Ahn, J. S., Park, K., & Ahn, M. (2017) · Oncotarget · doi:10.18632/oncotarget.18728 · Cited by 38
Metformin with Everolimus and Octreotide in Pancreatic Neuroendocrine Tumor Patients with Diabetes
Pusceddu, S., Buzzoni, R., Vernieri, C., Concas, L., Marceglia, S. R. F., Giacomelli, L., Milione, M., Leuzzi, L., Femia, D., Formisano, B., et al. (2016) · Future Oncology · doi:10.2217/fon-2015-0077 · Cited by 38
Bağcı, U., Foster, B. H., Miller-Jaster, K., Luna, B. M., Dey, B., Bishai, W. R., Jonsson, C. B., Jain, S. K., & Mollura, D. J. (2013) · EJNMMI Research · doi:10.1186/2191-219x-3-55 · Cited by 37
“In another study, [5], genetically engineered mouse models with non-small-cell lung cancer were used to question the molecular complexity of mixed therapeutic response.”
BackgroundMethodZhang, H., Shao, H., Golubovskaya, V., Chen, H., Cance, W. G., Adjei, A. A., & Dy, G. K. (2016) · British Journal of Cancer · doi:10.1038/bjc.2016.190 · Cited by 38
“This may provide mechanistic explanation for the observation that inactivation of the tumour suppressor LKB1 results in greater propensity for metastasis compared with loss of other tumour suppressors in a KRAS-driven murine lung cancer model (Chen et al, 2012).”
BackgroundDrosten, M., Guerra, C. E., & Barbacid, M. (2017) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a031542 · Cited by 43
“Another coclinical trial showed that treatment with the MEK inhibitor Selumetinib in combination with chemotherapy was beneficial only in K-Rasþ/LSLG12D or in compound K-Rasþ/LSLG12D;p53lox/lox mice, but not in K-Rasþ/LSLG12D;Lkb1 lox/lox animals, thus indicating that loss of Lkb1 modified the therapeutic response (Ch…”
BackgroundHynds, R. E., Huebner, A., Pearce, D. R., Hill, M. S., Akarca, A. U., Moore, D. A., Ward, S., Gowers, K. H. C., Karasaki, T., Bakir, M. A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-47547-3 · Cited by 36
Liu, J., Gao, L., Zhang, H., Wang, D., Wang, M., Zhu, J., Pang, C., & Wang, C. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m113.450106 · Cited by 37
“Thus, early diagnosis of patients who develop lung cancer metastasis could reduce the mortality and morbidity associated with this disease (3, 4).”
BackgroundTchaicha, J. H., Akbay, E. A., Altabef, A. B., Mikse, O. R., Kikuchi, E., Rhee, K., Liao, R. G., Bronson, R. T., Sholl, L. M., Meyerson, M. M., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-13-3218 · Cited by 37
Self-citationPerez, B. A., Ghafoori, A. P., Lee, C., Johnston, S. M., Li, Y., Moroshek, J. G., Ma, Y., Mukherjee, S., Kim, Y., Badea, C. T., et al. (2013) · Frontiers in Oncology · doi:10.3389/fonc.2013.00072 · Cited by 36
“Others have shown that such GEMMs of lung cancer may more faithfully predict the response of human lung cancers to systemic therapy (Singh et al., 2010; Chen et al., 2012).”
BackgroundSelf-citationOverview of Genetically Engineered Mouse Models of Distinct Breast Cancer Subtypes
Usary, J., Darr, D. B., Pfefferle, A. D., & Perou, C. M. (2016) · Current Protocols in Pharmacology · doi:10.1002/0471141755.ph1438s72 · Cited by 38
“Previous groups have identified the value of establishing “co-clinical” trials, where validated in vivo models are used to expedite drug discovery and to identify sensitive sub-populations of patients (Nardella et al., 2011; Chen et al., 2012; Lunardi et al., 2013).”
Background
Metadata
- Authors
- Chen, Z., Cheng, K., Walton, Z., Wang, Y., Ebi, H., Shimamura, T., Liu, Y., Tupper, T., Ouyang, J., Li, J., Gao, P., Woo, M. S., Xu, C., Yanagita, M., Altabef, A., Wang, S., Lee, C., Nakada, Y., Peña, C. G., Sun, Y., Franchetti, Y., Yao, C., Saur, A., Cameron, M. D., Nishino, M., Hayes, D. N., Wilkerson, M. D., Roberts, P. J., Lee, C. B., Bardeesy, N., Butaney, M., Chirieac, L. R., Costa, D. B., Jackman, D., Sharpless, N. E., Castrillon, D. H., Demetri, G. D., Jänne, P. A., Pandolfi, P. P., Cantley, L. C., Kung, A. L., Engelman, J. A., & Wong, K.-K.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Loyola University Chicago (US)
- Iowa State University (US)
- University of North Carolina at Chapel Hill (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Scripps Research Institute (US)
- Massachusetts General Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Boston Children's Hospital (US)
- Corresponding author
- Kung, Andrew L.
- Engelman, Jeffrey A.
- Wong, Kwok-Kin
- ORCID
- Cheng, Katherine
- Walton, Zandra
- Wang, Yuchuan
- Ebi, Hiromichi
- Shimamura, Takeshi
- Liu, Yan
- Ouyang, Jing
- Gao, Peng
- Xu, Chunxiao
- Yanagita, Masahiko
- Wang, Shumei
- Lee, Charles
- Nakada, Yuji
- Sun, Yanping
- Franchetti, Yoko
- Cameron, Michael D.
- Nishino, Mizuki
- Hayes, D. Neil
- Wilkerson, Matthew D.
- Roberts, Patrick J.
- Lee, Carrie B.
- Bardeesy, Nabeel
- Butaney, Mohit
- Chirieac, Lucian R.
- Costa, Daniel B.
- Sharpless, Norman E.
- Demetri, George D.
- Pandolfi, Pier Paolo
- Cantley, Lewis C.
- Kung, Andrew L.
- Engelman, Jeffrey A.
- Wong, Kwok-Kin
- Venue
- Nature
- Published
- 2012-03
- Volume
- 483
- Issue
- 7391
- Pages
- 613-617
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3385933
- OpenAlex
- W2094207365
- Cited by
- 446
- References
- 30
- Citations by year
- 2026: 10 · 2025: 7 · 2024: 8 · 2023: 27 · 2022: 13 · 2021: 30 · 2020: 21 · 2019: 29 · 2018: 31 · 2017: 35 · 2016: 42 · 2015: 55 · 2014: 58 · 2013: 62 · 2012: 18
- FWCI
- 49.79
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- American Lung Association
- National Institutes of Health (5k23ca157631-02)
- National Cancer Institute (CA137181, R01CA166480, K23-CA157631, RC2CA147940, R01CA122794, R01CA140594, CA 140594, P50CA090578, CA147940, CA 122794, R01CA137181, CA137008-01, R01CA163896, P01CA120964, R01CA137008, P30CA016086, U01CA141576, CA137008)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- lung cancer, KRAS-mutant lung cancer, co-clinical trials, docetaxel, selumetinib, MEK inhibitors, combination therapy, TP53 mutation, tumor suppressor loss, chemoresistance
- MeSH terms
- Docetaxel, Animals, Antineoplastic Combined Chemotherapy Protocols, Benzimidazoles, Disease Models, Animal, Drug Evaluation, Preclinical, Humans, Lung Neoplasms, Mutation, Pharmacogenetics, Proto-Oncogene Proteins, Tomography, X-Ray Computed, Biomarkers, Tumor, Reproducibility of Results, Randomized Controlled Trials as Topic, Genes, p53, Proto-Oncogene Proteins p21(ras), Treatment Outcome, Clinical Trials, Phase II as Topic, Protein Serine-Threonine Kinases, ras Proteins, Fluorodeoxyglucose F18, Mitogen-Activated Protein Kinase Kinases, MAP Kinase Signaling System, Taxoids, Positron-Emission Tomography, Mice, AMP-Activated Protein Kinases
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