Abstract 4470: Mechanisms of acquired resistance to the PI3K inhibitors in colorectal cancer cell lines.

Abstract

Abstract Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene or loss of the tumor suppressor PTEN. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K is a promising therapeutic target for cancer. There are multiple PI3K inhibitors in clinical trials and the current study investigates preclinical mechanisms of resistance to two clinical PI3K inhibitors, GDC-0941 and GDC 0032. Acquired resistance to PI3K inhibitors was generated in vitro, in SW48 parental and SW48 knock-in clones harboring hotspot PIK3CA mutations. We found that GDC-0941 resistant clones and GDC-0032 resistant clones demonstrated a marked signaling increase in the PI3K/Akt/mTOR pathway when released from drug inhibition, and different nodes in the pathway were activated. GDC-0941 resistant clones have elevated pAKT levels due to loss of PTEN, and the pAKT is further increased when drug is removed. GDC-0032 resistant clones retained functional PTEN protein, but had increased pS6 levels in the absence of GDC-0032. The result of increased PI3K pathway signaling in cells with acquired resistance to PI3K inhibitors resulted in a decreased sensitivity to inhibitors of the MAPK pathway upon removal of drug. Resistant cells maintained on PI3K inhibitors gained sensitivity to MAPK pathway inhibitors. These preclinical data may provide rationale for combination therapy in the clinic. Citation Format: Kyle A. Edgar, Marie-Claire Wagle, Yibing Yan, Marcia Belvin, Lori Friedman, Jeffrey Wallin. Mechanisms of acquired resistance to the PI3K inhibitors in colorectal cancer cell lines. [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 4470. doi:10.1158/1538-7445.AM2013-4470