Murine Co-Clinical Trials May Inform Human Clinical Trials

Preclinical studies have suggested that MEK inhibitors may be effective in KRAS-mutant non–small cell lung cancer (NSCLC). A clinical trial was therefore initiated to compare docetaxel monotherapy, the standard of care for NSCLC, with docetaxel combined with the MEK inhibitor selumetinib in patients with KRAS-mutant tumors. Chen and colleagues conducted a simultaneous “co-clinical” trial in genetically engineered mouse models of Kras-mutant lung cancer to identify cooperating genetic events that may affect the outcome of the human trial. The authors found that tumors with mutations in p53 or Lkb1 in addition to Kras were largely unresponsive to docetaxel monotherapy and more likely to progress than were tumors harboring only a Kras mutation. Combined docetaxel and selumetinib treatment, however, led to an overall response rate of 92% in Kras-mutant tumors and a 61% overall response rate in Kras/p53-mutant tumors, but only a 33% overall response rate in Kras/Lkb1-mutant tumors. The authors observed relatively low baseline levels of ERK phosphorylation in Kras/Lkb1-mutant murine lung cancers, suggesting that these tumors may be resistant to selumetinib because they are not dependent on high levels of MEK activity. Positron emission tomography revealed that the Kras/Lkb1-mutant murine tumors, as well as human KRAS-mutant lung cancers with low LKB1 levels, also had a higher uptake of ¹⁸F-fluoro-2-deoxy-glucose (FDG), identifying FDG–PET imaging as a possible biomarker strategy to predict poor response to docetaxel and selumetinib. Together, these findings predict that combination therapy with selumetinib and docetaxel will prove superior to standard-of-care therapy in patients with KRAS-mutant NSCLC but that this benefit may be blunted in patients with coexisting mutation of LKB1. The authors advocate for addressing this hypothesis through retroactive analysis of the concurrent human clinical trial, or prospectively in future trials.

Chen Z, Cheng K, Walton Z, Wang Y, Ebi H, Shimamura T, et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 2012;483:613–7.

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