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 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.

DOI: 10.1038/nature10937

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@article{Chen2012AML, title={A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response.}, author={Zhao Chen and Katherine A. Cheng and Zandra E. Walton and Yuchuan Wang and H Ebi and Takeshi Shimamura and Yan Liu and Tanya Tupper and Jing Ping Ouyang and Jie Li and Peng Gao and Michele S. Woo and Chunxiao Xu and Masahiko Yanagita and Abigail B Altabef and Shumei Wang and Charles Tzu-Chi Lee and Yuji Nakada and Christopher G. Pe{\~n}a and Yanping Sun and Yoko Franchetti and Catherine Yao and Amy M. Saur and Michael Cameron and Mizuki Nishino and D. Neil Hayes and Matthew D. Wilkerson and Patrick J. Roberts and Carrie B. Lee and Nabeel Bardeesy and Mohit Butaney and Lucian R . Chirieac and Daniel Botelho Costa and David Jackman and Norman E Sharpless and Diego H. Castrillon and George Daniel Demetri and Pasi Antero J{\"a}nne and Pier Paolo Pandolfi and Lewis C. Cantley and Andrew L Kung and Jeffrey A. Engelman and Kwok-kin Wong}, journal={Nature}, year={2012}, volume={483 7391}, pages={613-7} }