Abstract 3278: A subset of non-small cell lung cancers with wild-type EGFR are sensitized to Erlotinib (EGFR TKI) by mTOR inhibition.
Authors: Britt Rebecca R. , Girard Luc , Yoo Hyuntae , Minna John 
Published: August 2014

To date, therapies targeting EGFR have only been effective in treating NSCLC patients whose tumors harbor a mutation in the EGFR gene. However, wild-type EGFR is often amplified in tumors and may still be an important, targetable driver even when no mutation is present. Continued activation of the PI3K-AKT-mTOR signaling pathway in the face of EGFR inhibition is a known indicator of resistance to EGFR targeted therapies. Therefore combination of an EGFR inhibitor with an inhibitor of the downstream kinase mTOR may be a useful strategy to overcome resistance to EGFR inhibition. In this study, the EGFR tyrosine kinase inhibitor, erlotinib, was used in combination with the dual mTORC1/2 inhibitor, Torin1, to screen a panel of NSCLC cell lines (N = 25) for a synergistic response to the combination of Torin1 + erlotinib verses each agent individually.

A subset of EGFR wild-type NSCLC cell lines (5/25) responded synergistically to the erlotinib/Torin1 combination. Several cell lines in this subset harbor mutations in the Ras oncogene and thus are resistant to EGFR targeting monotherapy. These lines are also resistant to Torin1 treatment as a single agent. The erlotinib/Torin1 combination did not induce apoptosis or alter the cell cycle profile of the sensitized cell lines, but rather appears to slow the rate of proliferation.

Other mTOR inhibitors such as the standard mTORC1 inhibitor, rapamycin, and the dual mTORC1/2 inhibitor AZD8055 sensitize these lines to erlotinib, but not to the same extent that Torin1 does. Erlotinib sensitive, EGFR mutant lines, and EGFR mutant lines with additional resistance mutations, are not sensitized to erlotinib with the addition of Torin1. The ability of Torin1 to sensitize lines appears to be specific for EGFR inhibition, as it does not sensitize these lines to standard Paclitaxel/Carboplatin doublet chemotherapy. We are exploring the possibility of feedback loops which are affected specifically by the Erlotinib/Torin1 combination, which may lead to the sensitization seen in these lines.

Several avenues are being explored in order to determine biomarkers which may be used to predict a synergistic response to combined erlotinib/Torin1 therapy. Gene expression (microarray) has provided a candidate list of genes that are highly up-/down-regulated specifically in the responding subset of cell lines. Additionally, an siRNA mini-library screen (targeting 54 genes) focusing on mTOR related genes and GC/MS analyses to determine differences in metabolite levels between cell lines and following treatments, are being used to examine the role of metabolic differences in determining response to erlotinib/Torin1 therapy. By determining metabolic biomarkers to predict a synergistic response to erlotinib/Torin1 therapy, we hope to expand the utility of EGFR targeting therapies to EGFR wild-type tumors in a predictable and clinically relevant manner.

Citation Format: Rebecca R. Britt, Luc Girard, Hyuntae Yoo, John Minna. A subset of non-small cell lung cancers with wild-type EGFR are sensitized to Erlotinib (EGFR TKI) by mTOR inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3278. doi:10.1158/1538-7445.AM2013-3278