Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms
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‐...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer Nature
2013-11-01
|
| Series: | Molecular Systems Biology |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/msb.2013.61 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849235712977666048 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Jiannong Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-bc792efbcc2c4d1ebd85fd51a06f5c26 |
| institution | Kabale University |
| issn | 1744-4292 |
| language | English |
| publishDate | 2013-11-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | Molecular Systems Biology |
| spelling | doaj-art-bc792efbcc2c4d1ebd85fd51a06f5c262025-08-20T04:02:41ZengSpringer NatureMolecular Systems Biology1744-42922013-11-019111910.1038/msb.2013.61Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanismsJiannong Li0Keiryn Bennett1Alexey Stukalov2Bin Fang3Guolin Zhang4Takeshi Yoshida5Isamu Okamoto6Jae‐Young Kim7Lanxi Song8Yun Bai9Xiaoning Qian10Bhupendra Rawal11Michael Schell12Florian Grebien13Georg Winter14Uwe Rix15Steven Eschrich16Jacques Colinge17John Koomen18Giulio Superti‐Furga19Eric B Haura20Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research InstituteCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesProteomics and Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research InstituteDepartment of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research InstituteCenter for Clinical and Translational Research, Kyushu University HospitalCenter for Clinical and Translational Research, Kyushu University HospitalDepartment of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research InstituteDepartment of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research InstituteDepartment of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research InstituteDepartment of Computer Science and Engineering, University of South FloridaBiostatistics Departments, H. Lee Moffitt Cancer Center and Research InstituteBiostatistics Departments, H. Lee Moffitt Cancer Center and Research InstituteCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesDrug Discovery Department, H. Lee Moffitt Cancer Center and Research InstituteDepartment of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research InstituteCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesProteomics and Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research InstituteCeMM Research Center for Molecular Medicine of the Austrian Academy of SciencesDepartment of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research InstituteAbstract 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.https://doi.org/10.1038/msb.2013.61epidermal growth factor receptorinteractomelung cancerproteomicstyrosine kinase inhibitor |
| spellingShingle | 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 Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms Molecular Systems Biology epidermal growth factor receptor interactome lung cancer proteomics tyrosine kinase inhibitor |
| title | Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms |
| title_full | Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms |
| title_fullStr | Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms |
| title_full_unstemmed | Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms |
| title_short | Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms |
| title_sort | perturbation of the mutated egfr interactome identifies vulnerabilities and resistance mechanisms |
| topic | epidermal growth factor receptor interactome lung cancer proteomics tyrosine kinase inhibitor |
| url | https://doi.org/10.1038/msb.2013.61 |
| work_keys_str_mv | AT jiannongli perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT keirynbennett perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT alexeystukalov perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT binfang perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT guolinzhang perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT takeshiyoshida perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT isamuokamoto perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT jaeyoungkim perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT lanxisong perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT yunbai perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT xiaoningqian perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT bhupendrarawal perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT michaelschell perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT floriangrebien perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT georgwinter perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT uwerix perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT steveneschrich perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT jacquescolinge perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT johnkoomen perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT giuliosupertifurga perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms AT ericbhaura perturbationofthemutatedegfrinteractomeidentifiesvulnerabilitiesandresistancemechanisms |