title: 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-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.
authors.affiliation: Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Jiannong
authors.initials: J
authors.lastname: Li
authors.forename: Keiryn
authors.initials: K
authors.lastname: Bennett
authors.forename: Alexey
authors.initials: A
authors.lastname: Stukalov
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.forename: Guolin
authors.initials: G
authors.lastname: Zhang
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Isamu
authors.initials: I
authors.lastname: Okamoto
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Lanxi
authors.initials: L
authors.lastname: Song
authors.forename: Yun
authors.initials: Y
authors.lastname: Bai
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Qian
authors.forename: Bhupendra
authors.initials: B
authors.lastname: Rawal
authors.forename: Michael
authors.initials: M
authors.lastname: Schell
authors.forename: Florian
authors.initials: F
authors.lastname: Grebien
authors.forename: Georg
authors.initials: G
authors.lastname: Winter
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.forename: Steven
authors.initials: S
authors.lastname: Eschrich
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.forename: John
authors.initials: J
authors.lastname: Koomen
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Eric B
authors.initials: EB
authors.lastname: Haura
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005663:Furans; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D060066:Protein Interaction Maps; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D019311:Staurosporine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C119379:lestaurtinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D019311:Staurosporine; C059539:midostaurin