Abstract 78: IGF-1R inhibition activates p70S6K1 to promote survival via MEK1/2 activation in colon cancer cells

Abstract

Abstract The insulin-like growth factor 1 receptor (IGF-1R) is a heterotetramer with tyrosine kinase activity, composed of two α subunits containing the ligand-binding site and two β subunits harboring the tyrosine kinase activity. Upon binding with ligands (IGF-1, IGF-2, and insulin), IGF-1R leads to activation of downstream pathways including PI3-K/AKT and Ras/MAPK, two frequently activated pathways for promoting cell survival and proliferation in various cancers including colorectal cancer. Immunohistochemical studies revealed that IGF-1R is over-expressed in colorectal cancer tissues compared to the adjacent normal tissues. Most importantly, a higher expression of IGF-1R is associated with a higher grade and stage in colorectal cancer patients. Since the IGF-1R signaling pathway plays an essential role in development, maintenance, and survival of tumors, many small molecule compounds and antibodies targeting IGF-1R have been developed. Unfortunately, these anti-IGF-1R agents demonstrate very limited efficacy in clinical trials, suggesting the existence of a mechanism to overcome the inhibitory effect of IGF-1R in cancer cells. In this study, we aim to understand the resistance mechanism of IGF-1R inhibition in colon cancer cells. Prolonged treatment of IGF-1R resistant colon cancer cells with IGF-1R inhibitors (OSI-906, BMS-754807, and GSK1838705A) stimulates p70S6K1 activation, a well-known kinase signaling for cell survival. We also found that p70S6K1 activation is independent of mutation of K-RAS and PIK3CA, frequently occurring in colorectal cancer. Genetic knockdown or pharmacologic inhibition of p70S6K1 efficiently suppresses cell viability in response to IGF-1R inhibition, indicating that p70S6K1 activation contributes to the survival of IGF-1R inhibitor-treated cells. In addition to the increased phosphorylation of p70S6K1, phosphorylation of MEK1/2 is also elevated in colon cancer cells with prolonged inhibition of IGF-1R. Knockdown of MEK1/2 results in reduction of p70S6K1 activation in response to IGF-1R inhibition and subsequently increases apoptosis, suggesting that MEK1/2 is involved in p70S6K1 activation for survival. Furthermore, the combination of BMS754807 and U0126, a MEK1/2 inhibitor, effectively decreases the cell viability and increases apoptosis. Our data suggest that inhibition of MEK1/2 enhances the anti-proliferation effects of IGF-1R inhibitors, pointing out a new direction for overcoming the resistance of IGF-1R inhibition in colorectal cancer. Citation Format: Qing Wang, Hsin-Sheng Yang. IGF-1R inhibition activates p70S6K1 to promote survival via MEK1/2 activation in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 78.