title: Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition.
abstract: Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Xiarong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Leiliane P
authors.initials: LP
authors.lastname: Sousa
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, CT 06511.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Mandel-Bausch
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Francisco
authors.initials: F
authors.lastname: Tome
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Andrey V
authors.initials: AV
authors.lastname: Reshetnyak
authors.affiliation: Kolltan Pharmaceuticals Inc., New Haven, CT 06511.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Hadari
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; irit.lax@yale.edu joseph.schlessinger@yale.edu.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; irit.lax@yale.edu joseph.schlessinger@yale.edu.
authors.forename: Irit
authors.initials: I
authors.lastname: Lax
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy*; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D047428:Protein Kinase Inhibitors; D019009:Proto-Oncogene Proteins c-kit
keywords: KIT; monoclonal antibody; oncogenic mutant; receptor tyrosine kinase; targeted therapy