Amphiregulin and PTEN Evoke a Multimodal Mechanism of Acquired Resistance to PI3K Inhibition

Overview

Journal Genes Cancer

Specialty Oncology

Date 2014 Jul 24

PMID 25053989

Citations 9

Authors

Kyle A Edgar

Lisa Crocker

Eric Cheng

Marie-Claire Wagle

Matthew Wongchenko

Yibing Yan

Timothy R Wilson

Nicholas Dompe

Richard M Neve

Marcia Belvin

Deepak Sampath

Lori S Friedman

Jeffrey J Wallin

Affiliations

Soon will be listed here.

Abstract

Phosphoinositide-3 kinase (PI3K) signaling pathway alterations occur broadly in cancer and PI3K is a promising therapeutic target. Here, we investigated acquired resistance to GDC-0941, a PI3K inhibitor in clinical trials. Colorectal cancer (CRC) cells made to be resistant to GDC-0941 were discovered to secrete amphiregulin, which resulted in increased EGFR/MAPK signaling. Moreover, prolonged PI3K pathway inhibition in cultured cells over a period of months led to a secondary loss of PTEN in 40% of the CRC lines with acquired resistance to PI3K inhibition. In the absence of PI3K inhibitor, these PTEN-null PI3K inhibitor-resistant clones had elevated PI3K pathway signaling and decreased sensitivity to MAPK pathway inhibitors. Importantly, PTEN loss was not able to induce resistance to PI3K inhibitors in the absence of amphiregulin, indicating a multimodal mechanism of acquired resistance. The combination of PI3K and MAPK pathway inhibitors overcame acquired resistance in vitro and in vivo.

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