title: Synthetic lethal screening reveals FGFR as one of the combinatorial targets to overcome resistance to Met-targeted therapy.
abstract: Met is a receptor tyrosine kinase that promotes cancer progression. In addition, Met has been implicated in resistance of tumors to various targeted therapies such as epidermal growth factor receptor inhibitors in lung cancers, and has been prioritized as a key molecular target for cancer therapy. However, the underlying mechanism of resistance to Met-targeting drugs is poorly understood. Here, we describe screening of 1310 genes to search for key regulators related to drug resistance to an anti-Met therapeutic antibody (SAIT301) by using a small interfering RNA-based synthetic lethal screening method. We found that knockdown of 69 genes in Met-amplified MKN45 cells sensitized the antitumor activity of SAIT301. Pathway analysis of these 69 genes implicated fibroblast growth factor receptor (FGFR) as a key regulator for antiproliferative effects of Met-targeting drugs. Inhibition of FGFR3 increased target cell apoptosis through the suppression of Bcl-xL expression, followed by reduced cancer cell growth in the presence of Met-targeting drugs. Treatment of cells with the FGFR inhibitors substantially restored the efficacy of SAIT301 in SAIT301-resistant cells and enhanced the efficacy in SAIT301-sensitive cells. In addition to FGFR3, integrin β3 is another potential target for combination treatment with SAIT301. Suppression of integrin β3 decreased AKT phosphorylation in SAIT301-resistant cells and restored SAIT301 responsiveness in HCC1954 cells, which are resistant to SAIT301. Gene expression analysis using CCLE database shows that cancer cells with high levels of FGFR and integrin β3 are resistant to crizotinib treatment, suggesting that FGFR and integrin β3 could be used as predictive markers for Met-targeted therapy and provide a potential therapeutic option to overcome acquired and innate resistance for the Met-targeting drugs.
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: B
authors.initials: B
authors.lastname: Kim
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: J M
authors.initials: JM
authors.lastname: Lee
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: Y
authors.initials: Y
authors.lastname: Jeong
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: T
authors.initials: T
authors.lastname: Ahn
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: D-S
authors.initials: DS
authors.lastname: Son
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: H W
authors.initials: HW
authors.lastname: Park
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: H-s
authors.initials: HS
authors.lastname: Yoo
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Song
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: E
authors.initials: E
authors.lastname: Lee
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: Y M
authors.initials: YM
authors.lastname: Oh
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: S B
authors.initials: SB
authors.lastname: Lee
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: J
authors.initials: J
authors.lastname: Choi
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Murray
authors.affiliation: Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: P H
authors.initials: PH
authors.lastname: Song
authors.affiliation: BioTherapeutics Lab, Samsung Advanced Institute of Technology (SAIT), Giheung-gu, Yongin-si, Gyeonggi-do, South Korea.
authors.forename: K-A
authors.initials: KA
authors.lastname: Kim
authors.affiliation: Lombardi Comprehensive Cancer Center, Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Weiner
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D019151:Peptide Library; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D017468:Receptors, Fibroblast Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C061248:ITGB3 protein, human; D039661:Integrin beta3; D019151:Peptide Library; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D034741:RNA, Small Interfering; D017468:Receptors, Fibroblast Growth Factor; C000597195:SAIT301; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met