Mass spectrometry–based proteomics reveals potential roles of NEK9 and MAP2K4 in resistance to PI3K inhibition in triple-negative breast cancers

Filip Mundt, Sandeep Rajput, Shunqiang Li, Kelly V. Ruggles, Arshag D. Mooradian, Philipp Mertins, Michael A. Gillette, Karsten Krug, Zhanfang Guo, Jeremy Hoog, Petra Erdmann-Gilmore, Tina Primeau, Shixia Huang, Dean P. Edwards, Xiaowei Wang, Xuya Wang, Emily Kawaler, D. R. Mani, Karl R. Clauser, Feng GaoJingqin Luo, Sherri R. Davies, Gary L. Johnson, Kuan lin Huang, Christopher J. Yoon, Li Ding, David Fenyo, Matthew J. Ellis, R. Reid Townsend, Jason M. Held, Steven A. Carr, Cynthia X. Ma

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Activation of PI3K signaling is frequently observed in triple-negative breast cancer (TNBC), 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 TNBC with varying responsiveness to buparlisib, a pan-PI3K inhibitor. In a subset of patient-derived xenografts, resistance was associated with incomplete inhibition of PI3K signaling and upregulated MAPK/MEK signaling in response to buparlisib. 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 vitro. A complex in/del frameshift in PIK3CA decreased sensitivity to buparlisib via NEK9/ MAP2K4–dependent mechanisms. In summary, our study supports a role for NEK9 and MAP2K4 in mediating buparlisib 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.

Original languageEnglish
Pages (from-to)2732-2746
Number of pages15
JournalCancer research
Volume78
Issue number10
DOIs
StatePublished - May 15 2018

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    Mundt, F., Rajput, S., Li, S., Ruggles, K. V., Mooradian, A. D., Mertins, P., Gillette, M. A., Krug, K., Guo, Z., Hoog, J., Erdmann-Gilmore, P., Primeau, T., Huang, S., Edwards, D. P., Wang, X., Wang, X., Kawaler, E., Mani, D. R., Clauser, K. R., ... Ma, C. X. (2018). Mass spectrometry–based proteomics reveals potential roles of NEK9 and MAP2K4 in resistance to PI3K inhibition in triple-negative breast cancers. Cancer research, 78(10), 2732-2746. https://doi.org/10.1158/0008-5472.CAN-17-1990