Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms |
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| Authors: | Jiannong Li Keiryn Bennett Alexey Stukalov Bin Fang Guolin Zhang Takeshi Yoshida Isamu Okamoto Jae‐Young Kim Lanxi Song Yun Bai Xiaoning Qian Bhupendra Rawal Michael Schell Florian Grebien Georg Winter Uwe Rix Steven Eschrich Jacques Colinge John Koomen Giulio Superti‐Furga Eric B Haura |
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| Affiliation: | 1. Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, , Tampa, FL, USA;2. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, , Vienna, Austria;3. Proteomics and Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, , Tampa, FL, USA;4. Center for Clinical and Translational Research, Kyushu University Hospital, , Fukuoka, Japan;5. Department of Computer Science and Engineering, University of South Florida, , Tampa, FL, USA;6. Biostatistics Departments, H. Lee Moffitt Cancer Center and Research Institute, , Tampa, FL, USA;7. Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, , Tampa, FL, USA;8. Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, , Tampa, FL, USA |
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| Abstract: | We hypothesized that elucidating the interactome of epidermal growth factor receptor (EGFR) forms that are mutated in lung cancer, via global analysis of protein–protein interactions, phosphorylation, and systematically perturbing the ensuing network nodes, should offer a new, more systems‐level perspective of the molecular etiology. Here, we describe an EGFR interactome of 263 proteins and offer a 14‐protein core network critical to the viability of multiple EGFR‐mutated lung cancer cells. Cells with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) had differential dependence of the core network proteins based on the underlying molecular mechanisms of resistance. Of the 14 proteins, 9 are shown to be specifically associated with survival of EGFR‐mutated lung cancer cell lines. This included EGFR, GRB2, MK12, SHC1, ARAF, CD11B, ARHG5, GLU2B, and CD11A. With the use of a drug network associated with the core network proteins, we identified two compounds, midostaurin and lestaurtinib, that could overcome drug resistance through direct EGFR inhibition when combined with erlotinib. Our results, enabled by interactome mapping, suggest new targets and combination therapies that could circumvent EGFR TKI resistance. |
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| Keywords: | epidermal growth factor receptor interactome lung cancer proteomics tyrosine kinase inhibitor |
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