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

    loading  Checking for direct PDF access through Ovid

Abstract

Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers1–4. 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 suppressors5–9, 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 withKRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244)10increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of eitherp53(also known asTp53) orLkb1(also known asStk11), two clinically relevant tumour suppressors6,9,11,12, markedly impaired the response ofKras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused byKrasandKrasandp53mutations, but mice withKrasandLkb1mutations 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.

Related Topics

    loading  Loading Related Articles