Abstract 239: Biomarker profiling and combination studies of receptor tyrosine kinase inhibitors of EGFR, ERBB2, IGFR-1, FGFR and PDGFR

Targeting Receptor Tyrosine Kinases (RTKs) for therapeutic efficacy has been a promising approach for modern oncological agents. However, not all cancers respond to these agents and understanding of the feedback and resistance mechanisms is not complete. We have used an In vitro cellular profiling of 240 genetically characterized tumor human cell lines to help understand genotypes that convey sensitivity and resistance to these agents. While most of the sensitive cell lines were unique to a given RTK inhibitor, many of the resistant cell lines had similar genotypes. We have investigated downstream genes for mutations, over-expression and phosphorylation status. Phosphorylation levels pAKT, pERK, and pJNK, and as well as basal levels of p27 KIP , EGFR and ERBB2 protein levels were analyzed. Many of the downstream mutations or activated genes confer resistance to the RTK inhibitors such as AKT, PTEN and PI3K mutations. In addition to downstream activation, we have found that overexpressed RTKs often seem to confer resistance to other RTK inhibitors. For example, EGFR over-expressed cell lines disproportionately populated the group of cell lines resistant to an IGFR-1 receptor agonist. We have investigated cross talk between these various RTKs. Both EGFR and IGFR-1 inhibitors were tested in a combinatorial approach through 60 cell lines for synergy and antagonism. We evaluate synergy calculations through combination index and bliss analysis across 60 cell lines. Other combinations are also in the process of being tested for synergy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 239. doi:10.1158/1538-7445.AM2011-239