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

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Abstract
In parallel with an ongoing human clinical trial, genetically engineered mouse models of lung cancer with different genetic alterations are treated with chemotherapeutic agents; the results have implications for the clinical trial. The idea of 'co-clinical' trials has been put forward as way of evaluating novel therapies. By testing a drug simultaneously in human clinical and mouse preclinical trials, the thinking is, the two sets of data can be combined to extract extra information. To demonstrate the potential of this approach, genetically engineered mouse models were used to mirror a randomized phase II clinical trial of the chemotherapeutic docetaxel in KRAS-driven lung cancer, comparing its action alone with that in combination with a MEK inhibitor. In the mouse model, tumours with Kras or Kras and p53 mutations were more responsive to the combination than to docetaxel alone, whereas mice carrying a deletion of Lkb1 in addition to activated Kras remained relatively unresponsive. This has important implications for the ongoing clinical trial, suggesting that patients should be tested for LKB1 mutations. 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.