Abstract A209: Predicting genetic drivers of MEK dependency with gene expression.

Inhibition of the RAS-RAF-MEK axis holds significant promise for targeted cancer therapy, highlighted by the recent clinical approval of BRAF (vemurafenib) and MEK (trametinib) inhibitors, and ongoing late-stage clinical trials for several other MEK inhibitors. All genetic aberrations resulting in pathway activation and dependency through which optimum patient populations may be selected are as yet not fully determined. Previously we published an 18-gene mRNA expression signature reproducibly predictive of MEK pathway output and response to MEK inhibition with selumetinib. Here we demonstrate that a 6-gene sub-signature shows enhanced reproducibility in cell lines, primary tumor explant in vivo models and fresh/fixed tissue samples, crossing tumor type and gene expression platforms. In published next-generation sequencing datasets we assessed pathway-linked genetic aberrations for their impact on MEK signature output. We show the potential for this signature to dissect MEK dependency amongst RAS mutant tumors. Furthermore we identify a number of genetic aberrations outside of BRAF and KRAS driving high MEK signature expression, including a synthetic lethal-like profile with NF1 deletion. The signature provides a robust and dynamic marker of MEK output applicable to clinical samples, and highlights a number of genetic opportunities to expand the clinical scope for MEK inhibitor based therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A209. Citation Format: Jonathan R. Dry, Darren Hodgson, Roz Brant, Tom Liptrot, Elizabeth Harrington, Carl Barrett, Paul D. Smith. Predicting genetic drivers of MEK dependency with gene expression. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A209.