Mass spectrometry-based proteomics reveals potential roles of NEK9 and MAP2K4 in resistance to PI3K inhibitors in triple-negative breast cancers
- 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.
- Gao, F.
- Luo, J.
- Davies, S.R.
- Johnson, G.L.
- Huang, K.L.
- Yoon, C.J.
- Ding, L.
- Fenyö, D.
- Ellis, M.J.
- Townsend, R.R.
- Held, J.M.
- Carr, S.A.
- Ma, C.X.
DOIAbstract
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 ...
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