Abstract PR06: CRISPR screens identified drivers of endocrine resistance and synthetic lethal vulnerabilities in breast cancer

Estrogen receptor positive (ER+) breast cancer is treated with endocrine therapies, although in advanced disease therapeutic resistance almost invariably develops. Using genome-wide CRISPR screens we identified genes essential for the growth of ER+ breast cancers. More importantly, we also identified genes whose loss confers endocrine resistance. Notably the expression of c-src tyrosine kinase (CSK) is driven by estrogen yet loss of CSK promoted estrogen independent growth. A synthetic lethality screen for CSK loss identified the p21 protein-activated kinase (PAK2) which becomes activated by SRC-family kinases (SFK) in the absence of CSK. CSK loss or PAK2 over-expression predict worse clinical outcome in breast cancer cohorts. Inhibitors of PAK2 or SFK block estrogen-independent breast tumor growth. These findings reveal an estrogen-induced negative feedback loop that constrains the growth of ER+ tumors thereby limiting the efficacy of therapies that inhibit ER and suggest a previously unappreciated therapeutic route to overcoming endocrine resistance. Citation Format: Tengfei Xiao, Wei Li, Xiaoqing Wang, Han Xu, Qiu Wu, Peng Jiang, Jixin Yang, Teng Fei, Chongzhi Zang, Qi Liao, Jonathan Rennhack, Eran Andrechek, Nanlin Li, Rinath Jeselsohn, Shirley X. Liu, Myles Brown. CRISPR screens identified drivers of endocrine resistance and synthetic lethal vulnerabilities in breast cancer [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr PR06.