Mass Spectrometry-Based Proteomics Reveals Potential Roles of NEK9 and MAP2K4 in Resistance to PI3K Inhibition in Triple-Negative Breast Cancers

Abstract

Activation of PI3K signaling is frequently observed in triple-negative breast cancer (INBC), yet PI3K inhibitors have shown limited clinical activity. To investigate intrinsic and adaptive mechanisms of resistance, we analyzed a panel of patient-derived xenograft models of 'NBC with varying responsiveness to sib, a pan-PI3K inhibitor. In a subset of patient-derived xenografis, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparhsib. Outlier phosphoproteome and kinome analyses identified novel candidates functionally important to buparlisib resistance, including NEK9 and MAP2K4. Knockdown of NEK9 or MAP2K4 reduced both baseline and feedback MAPK/MEK signaling and showed synthetic lethality with buparlisib in Wm. A complex in/del frantesliift in PIK3CA decreased sensitivity to buparlisib via NEK9/MAP2K4 -dependent mechanisms. In summary, our study supports a role for NEK9 and MAP2K4 in mediating bupadisib resistance and demonstrates the value of unbiased omic analyses in uncovering resistance mechanisms to targeted therapy. Significance: Integrative phosphoproteogenomic analysis is used to determine intrinsic resistance mechanisms of triple-negative breast tumors to PI3K inhibition. (C) 2018 AACR.