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PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer

Costa, Carlotta and Ly, Amy and Walmsley, Charlotte S. and Huynh, Tiffany and Healy, Christopher and Peterson, Rachel and Jakubik, Charles T. and Henderson, Laura E. and Ho, Jeffrey and Timotina, Daria and Sanidas, Ioannis and Veloso, Artur and Mino-Kenudson, Mari and Stone, James R. and Dyson, Nick and Benes, Cyril H. and Engelman, Jeffrey and Dejan, Juric (2019) PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kα inhibitors in breast cancer. Cancer discovery. ISSN 21598290

Abstract

The combination of CDK4/6 inhibitors with anti-estrogen therapies significantly improves clinical outcomes in ER-positive advanced breast cancer. To identify mechanisms of acquired resistance, we analyzed serial biopsies and rapid autopsies from patients treated with the combination of the CDK4/6 inhibitor ribociclib with letrozole. This study revealed that some resistant tumors acquired RB loss, whereas other tumors lost PTEN expression at the time of progression. In breast cancer cells ablation of PTEN, through increased AKT activation, was sufficient to promote resistance to CDK4/6 inhibition in vitro and in vivo. Mechanistically, PTEN loss resulted in exclusion of p27 from the nucleus, leading to increased activation of both CDK4 and CDK2. Since PTEN loss also causes resistance to PI3Kalpha-inhibitors, currently approved in the post-CDK4/6 setting, these findings provide critical insight into how this single genetic event may cause clinical cross-resistance to multiple targeted therapies in the same patient, with implications for optimal treatment sequencing strategies.

Item Type: Article
Date Deposited: 03 Dec 2019 00:45
Last Modified: 03 Dec 2019 00:45
URI: https://oak.novartis.com/id/eprint/35120

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