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

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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.

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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.

Author information

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.

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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