title: Rescue screens with secreted proteins reveal compensatory potential of receptor tyrosine kinases in driving cancer growth.
abstract: The overall power of kinase inhibitors is substantially overshadowed by the acquisition of drug resistance. To address this issue, we systematically assessed the potential of secreted proteins to induce resistance to kinase inhibitors. To this end, we developed a high-throughput platform for screening a cDNA library encoding 3,432 secreted proteins in cellular assays. Using cancer cells originally dependent on either MET, FGFR2, or FGFR3, we observed a bypass of dependence through ligand-mediated activation of alternative receptor tyrosine kinases (RTK). Our findings indicate a broad and versatile potential for RTKs from the HER and FGFR families as well as MET to compensate for loss of each other. We further provide evidence that combined inhibition of simultaneously active RTKs can lead to an added anticancer effect.
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Harbinski
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Craig
authors.forename: Sneha
authors.initials: S
authors.lastname: Sanghavi
authors.forename: Douglas
authors.initials: D
authors.lastname: Jeffery
authors.forename: Lijuan
authors.initials: L
authors.lastname: Liu
authors.forename: Kelly Ann
authors.initials: KA
authors.lastname: Sheppard
authors.forename: Sabrina
authors.initials: S
authors.lastname: Wagner
authors.forename: Christelle
authors.initials: C
authors.lastname: Stamm
authors.forename: Andreas
authors.initials: A
authors.lastname: Buness
authors.forename: Christian
authors.initials: C
authors.lastname: Chatenay-Rivauday
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.forename: Feng
authors.initials: F
authors.lastname: He
authors.forename: Chris X
authors.initials: CX
authors.lastname: Lu
authors.forename: Vito
authors.initials: V
authors.lastname: Guagnano
authors.forename: Thomas
authors.initials: T
authors.lastname: Metz
authors.forename: Peter M
authors.initials: PM
authors.lastname: Finan
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Porter
authors.forename: Vic E
authors.initials: VE
authors.lastname: Myer
authors.forename: Diana
authors.initials: D
authors.lastname: Graus-Porta
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilson
authors.forename: Alan
authors.initials: A
authors.lastname: Buckler
authors.forename: Ralph
authors.initials: R
authors.lastname: Tiedt
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous
chemical_list: D066246:ErbB Receptors; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D051497:Receptor, Fibroblast Growth Factor, Type 2; D051498:Receptor, Fibroblast Growth Factor, Type 3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C496353:FGFR2 protein, human; C496365:FGFR3 protein, human; C491743:MET protein, human