Dataset Information

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 (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. Cancer Res; 78(10); 2732-46. ©2018 AACR.

SUBMITTER: Mundt F

PROVIDER: S-EPMC5955814 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Publications

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

Mundt Filip F Rajput Sandeep S Li Shunqiang S Ruggles Kelly V KV Mooradian Arshag D AD Mertins Philipp P Gillette Michael A MA Krug Karsten K Guo Zhanfang Z Hoog Jeremy J Erdmann-Gilmore Petra P Primeau Tina T Huang Shixia S Edwards Dean P DP Wang Xiaowei X Wang Xuya X Kawaler Emily E Mani D R DR Clauser Karl R KR Gao Feng F Luo Jingqin J Davies Sherri R SR Johnson Gary L GL Huang Kuan-Lin KL Yoon Christopher J CJ Ding Li L Fenyö David D Ellis Matthew J MJ Townsend R Reid RR Held Jason M JM Carr Steven A SA Ma Cynthia X CX

Cancer research 20180222 10

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 resp ...[more]

PMID: 29472518

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Project description:Filip Mundt, Sandeep Rajput, Shunqiang Li, Kelly Ruggles, Arshag D. Mooradian, Philipp Mertins, Michael A. Gillette, Karsten Krug, et al., Cancer Res. 2018 May 15;78(10):2732-2746. doi: 10.1158/0008-5472.CAN-17-1990.Activation of phosphoinositide 3-kinase (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.Mass spectra files contributing to this study can be downloaded in the original instrument vendor format (see Data Sets below). Metadata files include protocols and mapping of specimens to TMT6 labels for each experiment.The protein database used to analyze mass spectrometry data files is also provided below (RefSeq.20130727-Human.20130730-MouseNR.mm13.fasta). This file includes the RefSeq database containing 31,767 human proteins, 24,821 mouse proteins, and 85 additional contaminants (RefSeq release 60, 2013/7/27-2013/7/30).<ul><li>Dataset imported into MassIVE from <a href="https://cptac-data-portal.georgetown.edu/cptac/s/S040">https://cptac-data-portal.georgetown.edu/cptac/s/S040</a> on 10/19/18</li></ul>

Dataset Information

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

Publications

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

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