Abstract 1986: RAS signaling is the key factor determining differential response to PI3K and MAPK targeting compounds in a panel of breast cancer cell lines

We have tested PI3K and MAPK targeting compounds in a panel of 69 breast cancer cell lines. Following the molecular stratification of breast cancer tumors, we have used ER and HER2 biomarkers to stratify cell lines into HER2 positive (HER2+), ER positive (ER+), and triple negative (TN; ER-, PR- and HER2-) subgroups. Both gene expression and response to compounds showed significant differences among the subtypes. Response to mTOR and AKT inhibition was the greatest in ER+ and HER2+ groups (86%, 85% for mTORi and 64%, 77% for AKTi response rates, respectively), whereas TN cell lines showed preferential sensitivity to MEK inhibition (30%). The combination of AKT plus MEK and mTOR plus MEK inhibitors showed synergy in TN tumors (56% and 80% response rates, respectively), particularly in the epithelial subgroup. We believe that RAS pathway deregulation, as reported by a gene expression signature of RAS activation, is the key latent variable that explains the difference in responses. This conclusion is based on pathway activation differences between subtypes. We observe that the TN group has both elevated PI3K and MAPK signaling, evident by high levels of RAS, pERK, and pMEK signatures, whereas the ER+/GGI+ group only has high levels of PI3K signaling. Thus, mTOR, AKT, or MEK alone is insufficient to inhibit the TN lines, whereas the combos are very effective. Finally, we have assessed the prevalence of the EMT and RAS signatures across subtypes of breast tumors. Similar to cell lines, the RAS signature is markedly higher in TN compared to ER+/GGI+ and, to a lesser extent, compared to HER2+ tumors. The EMT signature on the other hand is not significantly different among subtypes. This would suggest that the response patterns observed in ER+/GGI+ and TN/E subtypes of this breast panel will be applicable to a substantial subpopulation of breast tumors (∼38%). Importantly, these breast subtypes represent the largest unmet need and are a high priority for the clinical oncology. 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 1986.