title: Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition.
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.
authors: Departments of Translational Oncology, South San Francisco, CA, USA.
authors: Kyle A
authors: KA
authors: Edgar
authors: Departments of Translational Oncology, South San Francisco, CA, USA.
authors: Lisa
authors: L
authors: Crocker
authors: Departments of Translational Oncology, South San Francisco, CA, USA.
authors: Eric
authors: E
authors: Cheng
authors: Department of Oncology Biomarkers, South San Francisco, CA, USA.
authors: Marie-Claire
authors: MC
authors: Wagle
authors: Department of Oncology Biomarkers, South San Francisco, CA, USA.
authors: Matthew
authors: M
authors: Wongchenko
authors: Department of Oncology Biomarkers, South San Francisco, CA, USA.
authors: Yibing
authors: Y
authors: Yan
authors: Department of Oncology Biomarkers, South San Francisco, CA, USA.
authors: Timothy R
authors: TR
authors: Wilson
authors: Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA.
authors: Nicholas
authors: N
authors: Dompe
authors: Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA.
authors: Richard M
authors: RM
authors: Neve
authors: Departments of Translational Oncology, South San Francisco, CA, USA.
authors: Marcia
authors: M
authors: Belvin
authors: Departments of Translational Oncology, South San Francisco, CA, USA.
authors: Deepak
authors: D
authors: Sampath
authors: Departments of Translational Oncology, South San Francisco, CA, USA.
authors: Lori S
authors: LS
authors: Friedman
authors: Departments of Translational Oncology, South San Francisco, CA, USA.
authors: Jeffrey J
authors: JJ
authors: Wallin
keywords: PI3K; PTEN; amphiregulin; drug resistance