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

Item Type:	Article
Title:	Mass spectrometry-based proteomics reveals potential roles of NEK9 and MAP2K4 in resistance to PI3K inhibitors in triple-negative breast cancers
Creators Name:	Mundt, F. and Rajput, S. and Li, S. and Ruggles, K.V. and Mooradian, A.D. and Mertins, P. and Gillette, M.A. and Krug, K. and Guo, Z. and Hoog, J. and Erdmann-Gilmore, P. and Primeau, T. and Huang, S. and Edwards, D.P. and Wang, X. and Wang, X. and Kawaler, E. and Mani, D.R. and Clauser, K.R. and Gao, F. and Luo, J. and Davies, S.R. and Johnson, G.L. and Huang, K.L. and Yoon, C.J. and Ding, L. and Fenyö, D. and Ellis, M.J. and Townsend, R.R. and Held, J.M. and Carr, S.A. and Ma, C.X.
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.
Keywords:	Aminopyridines, Antineoplastic Agents, Class I Phosphatidylinositol 3-Kinases, MAP Kinase Kinase 4, Mass Spectrometry, Morpholines, NIMA-Related Kinases, Proteomics, RNA Interference, Signal Transduction, Small Interfering RNA, Triple Negative Breast Neoplasms, Tumor Cell Line, Xenograft Model Antitumor Assays, Animals, Mice
Source:	Cancer Research
ISSN:	0008-5472
Publisher:	American Association for Cancer Research
Volume:	78
Number:	10
Page Range:	2732-2746
Date:	May 2018
Official Publication:	https://doi.org/10.1158/0008-5472.CAN-17-1990
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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