Amphiregulin and PTEN evoke a multimodal mechanism of acquired resistance to PI3K inhibition
Kyle A. Edgar1, Lisa Crocker1, Eric Cheng1, Marie-Claire Wagle2, Matthew Wongchenko2, Yibing Yan2, Timothy R. Wilson2, Nicholas Dompe3, Richard M. Neve3, Marcia Belvin1, Deepak Sampath1, Lori S. Friedman1 and Jeffrey J. Wallin1
1 Departments of Translational Oncology, South San Francisco, CA, USA
2 Department of Oncology Biomarkers, South San Francisco, CA, USA
3 Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA
Correspondence:
Jeffrey J. Wallin, email:
Keywords: PI3K, drug resistance, PTEN, amphiregulin
Received: May 3, 2014 Accepted: May 16, 2014 Published: May 17, 2014
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.
