Genetically activated oncogenes induce dependency on the constitutively activated oncoprotein in cancer cells. Targeted therapeutics that shut down the oncogenic signaling, induce apoptosis and thus lead to tumor shrinkage in patients can exploit this dependency. However, efficacy of single-agent inhibition often is limited by release of negative feedback loops or incomplete suppression of its primary target at clinically relevant concentrations.

The lack of preclinical models that capture the genomic diversity of human tumors impedes the transition from preclinical drug discovery to clinical trials lies in and this diversity. We sought to overcome these limitations and therefore we established a panel of 84 non-small cell lung cancer cell lines and characterized in depth in gene copy number, gene expression and mutation space.

We applied a chemo-genomics approach in order to determine the efficacy of single-agent and combination treatment with PI3K-, MAPK- and receptor tyrosine kinase (RTK-) inhibitors in genotypically defined subsets of tumor cells. We found RTK-driven tumors to largely depend on PI3K and RAS-/ RAF-driven tumors to be addicted to the MAPK signaling pathways, respectively. However, release of negative feedback loops led to activation of the alternate pathway. Combined inhibition of PI3K- and MAPK-pathways potently suppressed release of negative feedback loops, thereby resulting in enhanced induction of apoptosis in tumor cells and tumor shrinkage in vivo. In the subset of EGFR mutated cells harboring the gatekeeper mutation T790M we found limited efficacy of single-agent treatment with irreversible EGFR inhibitors. This limited activity could be linked to decreased binding velocity to the mutant kinase. However combined treatment of T790M-mutant tumor cells with irreversible ERBB inhibitors, and PI3K/mTOR inhibitors led to induction of apoptosis. Recently we established a systematic screening pipeline for the study of combined inhibition of key nodules of oncogenic signaling pathways and preliminary results suggest a critical role of PI3K/mTOR-signaling for efficacy of combination therapies. Overall our approach builds a robust framework for the preclinical study of combination therapies and might help to direct future drug development and patient stratification in clinical trials.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2189.