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.
| Original language | English |
|---|---|
| Article number | 705 |
| Journal | Molecular Systems Biology |
| Volume | 9 |
| DOIs | |
| Publication status | Published - Nov 5 2013 |
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All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Immunology and Microbiology(all)
- Agricultural and Biological Sciences(all)
- Applied Mathematics
Cite this
Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms. / Li, Jiannong; Bennett, Keiryn; Stukalov, Alexey; Fang, Bin; Zhang, Guolin; Yoshida, Takeshi; Okamoto, Isamu; Kim, Jae Young; Song, Lanxi; Bai, Yun; Qian, Xiaoning; Rawal, Bhupendra; Schell, Michael; Grebien, Florian; Winter, Georg; Rix, Uwe; Eschrich, Steven; Colinge, Jacques; Koomen, John; Superti-Furga, Giulio; Haura, Eric B.
In: Molecular Systems Biology, Vol. 9, 705, 05.11.2013.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Perturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms
AU - Li, Jiannong
AU - Bennett, Keiryn
AU - Stukalov, Alexey
AU - Fang, Bin
AU - Zhang, Guolin
AU - Yoshida, Takeshi
AU - Okamoto, Isamu
AU - Kim, Jae Young
AU - Song, Lanxi
AU - Bai, Yun
AU - Qian, Xiaoning
AU - Rawal, Bhupendra
AU - Schell, Michael
AU - Grebien, Florian
AU - Winter, Georg
AU - Rix, Uwe
AU - Eschrich, Steven
AU - Colinge, Jacques
AU - Koomen, John
AU - Superti-Furga, Giulio
AU - Haura, Eric B.
PY - 2013/11/5
Y1 - 2013/11/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84889244041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84889244041&partnerID=8YFLogxK
U2 - 10.1038/msb.2013.61
DO - 10.1038/msb.2013.61
M3 - Article
VL - 9
JO - Molecular Systems Biology
JF - Molecular Systems Biology
SN - 1744-4292
M1 - 705
ER -