Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers1,2,3,4. 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 therapy1,3. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors5,6,7,8,9, 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)10 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 suppressors6,9,11,12, 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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Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002)
Huang, M. E. et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72, 567–572 (1988)
Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010)
Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009)
Ahrendt, S. A. et al. p53 mutations and survival in stage I non-small-cell lung cancer: results of a prospective study. J. Natl. Cancer Inst. 95, 961–970 (2003)
Gill, R. K. et al. Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene 30, 3784–3791 (2011)
Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007)
Nagata, Y. et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6, 117–127 (2004)
Steels, E. et al. Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis. Eur. Respir. J. 18, 705–719 (2001)
Yeh, T. C. et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin. Cancer Res. 13, 1576–1583 (2007)
Matsumoto, S. et al. Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene 26, 5911–5918 (2007)
Weir, B. A. et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 450, 893–898 (2007)
Douillard, J. Y. et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J. Clin. Oncol. 28, 744–752 (2010)
Mascaux, C. et al. The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br. J. Cancer 92, 131–139 (2005)
Ji, H. et al. Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models. Cancer Res. 67, 4933–4939 (2007)
Verhoeven, D., Teijaro, J. R. & Farber, D. L. Pulse-oximetry accurately predicts lung pathology and the immune response during influenza infection. Virology 390, 151–156 (2009)
Li, D. et al. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI-272 and rapamycin combination therapy. Cancer Cell 12, 81–93 (2007)
Dykes, D. J., Bissery, M. C., Harrison, S. D., Jr & Waud, W. R. Response of human tumor xenografts in athymic nude mice to docetaxel (RP 56976, Taxotere). Invest. New Drugs 13, 1–11 (1995)
Engelman, J. A. et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nature Med. 14, 1351–1356 (2008)
Berghmans, T. et al. Primary tumor standardized uptake value (SUVmax) measured on fluorodeoxyglucose positron emission tomography (FDG-PET) is of prognostic value for survival in non-small cell lung cancer (NSCLC): a systematic review and meta-analysis (MA) by the European Lung Cancer Working Party for the IASLC Lung Cancer Staging Project. J. Thorac. Oncol. 3, 6–12 (2008)
Vansteenkiste, J. F. et al. Prognostic importance of the standardized uptake value on 18F-fluoro-2-deoxy-glucose-positron emission tomography scan in non-small-cell lung cancer: an analysis of 125 cases. Leuven Lung Cancer Group. J. Clin. Oncol. 17, 3201–3206 (1999)
Carretero, J. et al. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell 17, 547–559 (2010)
Hainsworth, J. D. et al. A phase II, open-label, randomized study to assess the efficacy and safety of AZD6244 (ARRY-142886) versus pemetrexed in patients with non-small cell lung cancer who have failed one or two prior chemotherapeutic regimens. J. Thorac. Oncol. 5, 1630–1636 (2010)
Erasmus, J. J., Rohren, E. & Swisher, S. G. Prognosis and reevaluation of lung cancer by positron emission tomography imaging. Proc. Am. Thorac. Soc. 6, 171–179 (2009)
Singh, M. et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nature Biotechnol. 28, 585–593 (2010)
Tuveson, D. & Hanahan, D. Translational medicine: cancer lessons from mice to humans. Nature 471, 316–317 (2011)
Politi, K. & Pao, W. How genetically engineered mouse tumor models provide insights into human cancers. J. Clin. Oncol. 29, 2273–2281 (2011)
Nishino, M. et al. CT tumor volume measurement in advanced non-small-cell lung cancer: Performance characteristics of an emerging clinical tool. Acad. Radiol. 18, 54–62 (2011)
Zhao, B. et al. A pilot study of volume measurement as a method of tumor response evaluation to aid biomarker development. Clin. Cancer Res. 16, 4647–4653 (2010)
LoRusso, P. M. et al. Phase I and pharmacokinetic study of lapatinib and docetaxel in patients with advanced cancer. J. Clin. Oncol. 26, 3051–3056 (2008)
This work is supported by the National Institutes of Health (CA122794, CA140594, CA137181, CA137008, CA147940, CA137008-01, 1U01CA141576, Lung SPORE P50CA090578), United against Lung Cancer Foundation, American Lung Association and Susan Spooner Research Fund.
N.H. and J.A.E. received research funding from AstraZenca. G.D.D. is a consultant of Champions Biotechnology. K.-K.W., N.E.S., P.A.J., N.B. and D.H.C. have filed a patent on LKB1 as a diagnostic biomarker in cancer. All other authors have no competing financial interest.
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