A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response

Abstract

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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Figure 1: Docetaxel and selumetinib combination therapy is more efficacious than docetaxel monotherapy in Kras and Kras/p53 lung cancers.
Figure 2: FDG-PET predicts treatment response.
Figure 3: Modulation of the MEK–ERK pathway in response to treatment is different across the three genotypes.
Figure 4: Long-term treatment outcome in Kras and Kras/p53 mice.

References

  1. 1

    Demetri, G. D. et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N. Engl. J. Med. 347, 472–480 (2002)

    CAS  Article  Google Scholar 

  2. 2

    Huang, M. E. et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72, 567–572 (1988)

    CAS  PubMed  Google Scholar 

  3. 3

    Maemondo, M. et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med. 362, 2380–2388 (2010)

    CAS  Article  Google Scholar 

  4. 4

    Mok, T. S. et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med. 361, 947–957 (2009)

    CAS  Article  Google Scholar 

  5. 5

    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)

    CAS  Article  Google Scholar 

  6. 6

    Gill, R. K. et al. Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene 30, 3784–3791 (2011)

    CAS  Article  Google Scholar 

  7. 7

    Ji, H. et al. LKB1 modulates lung cancer differentiation and metastasis. Nature 448, 807–810 (2007)

    ADS  CAS  Article  Google Scholar 

  8. 8

    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)

    CAS  Article  Google Scholar 

  9. 9

    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)

    CAS  Article  Google Scholar 

  10. 10

    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)

    CAS  Article  Google Scholar 

  11. 11

    Matsumoto, S. et al. Prevalence and specificity of LKB1 genetic alterations in lung cancers. Oncogene 26, 5911–5918 (2007)

    CAS  Article  Google Scholar 

  12. 12

    Weir, B. A. et al. Characterizing the cancer genome in lung adenocarcinoma. Nature 450, 893–898 (2007)

    ADS  CAS  Article  Google Scholar 

  13. 13

    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)

    CAS  Article  Google Scholar 

  14. 14

    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)

    CAS  Article  Google Scholar 

  15. 15

    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)

    CAS  Article  Google Scholar 

  16. 16

    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)

    CAS  Article  Google Scholar 

  17. 17

    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)

    CAS  Article  Google Scholar 

  18. 18

    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)

    CAS  Article  Google Scholar 

  19. 19

    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)

    CAS  Article  Google Scholar 

  20. 20

    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)

    Article  Google Scholar 

  21. 21

    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)

    CAS  Article  Google Scholar 

  22. 22

    Carretero, J. et al. Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell 17, 547–559 (2010)

    CAS  Article  Google Scholar 

  23. 23

    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)

    Article  Google Scholar 

  24. 24

    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)

    Article  Google Scholar 

  25. 25

    Singh, M. et al. Assessing therapeutic responses in Kras mutant cancers using genetically engineered mouse models. Nature Biotechnol. 28, 585–593 (2010)

    CAS  Article  Google Scholar 

  26. 26

    Tuveson, D. & Hanahan, D. Translational medicine: cancer lessons from mice to humans. Nature 471, 316–317 (2011)

    ADS  CAS  Article  Google Scholar 

  27. 27

    Politi, K. & Pao, W. How genetically engineered mouse tumor models provide insights into human cancers. J. Clin. Oncol. 29, 2273–2281 (2011)

    CAS  Article  Google Scholar 

  28. 28

    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)

    Article  Google Scholar 

  29. 29

    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)

    CAS  Article  Google Scholar 

  30. 30

    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)

    CAS  Article  Google Scholar 

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Acknowledgements

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.

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Z.C., K.C., Z.W., Y.W., H.E., T.S., Y.L., T.T., J.O., J.L., P.G., M.S.W., C.X., M.Y., A.A., S.W., C.L., Y.N., C.G.P., Y.S., Y.F., C.Y., A.S., M.D.C., D.N.H., M.D.W., P.J.R., C.B.L., N.B., N.E.S., D.H.C., G.D.D., P.A.J., L.C.C., C.B.L., M.N. and P.P.P. performed experimental work and data analyses. M.B., L.R.C., D.B.C. and D.J. collected data and provided patient materials. A.L.K., J.A.E. and K.-K.W. conceived and supervised all aspects of the project. All authors contributed to the final manuscript.

Corresponding authors

Correspondence to Andrew L. Kung or Jeffrey A. Engelman or Kwok-Kin Wong.

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Competing interests

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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Chen, Z., Cheng, K., Walton, Z. et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483, 613–617 (2012). https://doi.org/10.1038/nature10937

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