title: A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors.
abstract: KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T-->C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.
authors.affiliation: Department of Sarcoma, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. llchen@ mdanderson.org
authors.forename: Lei L
authors.initials: LL
authors.lastname: Chen
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Trent
authors.forename: Elsie F
authors.initials: EF
authors.lastname: Wu
authors.forename: Gregory N
authors.initials: GN
authors.lastname: Fuller
authors.forename: Latha
authors.initials: L
authors.lastname: Ramdas
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Austin K
authors.initials: AK
authors.lastname: Raymond
authors.forename: Victor G
authors.initials: VG
authors.lastname: Prieto
authors.forename: Caroline O
authors.initials: CO
authors.lastname: Oyedeji
authors.forename: Kelly K
authors.initials: KK
authors.lastname: Hunt
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
authors.forename: Barry W
authors.initials: BW
authors.lastname: Feig
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Hayes
authors.forename: Haesun
authors.initials: H
authors.lastname: Choi
authors.forename: Homer A
authors.initials: HA
authors.lastname: Macapinlac
authors.forename: Walter
authors.initials: W
authors.lastname: Hittelman
authors.forename: Marco A
authors.initials: MA
authors.lastname: Velasco
authors.forename: Shreyaskumar
authors.initials: S
authors.lastname: Patel
authors.forename: Michael A
authors.initials: MA
authors.lastname: Burgess
authors.forename: Robert S
authors.initials: RS
authors.lastname: Benjamin
authors.forename: Marsha L
authors.initials: ML
authors.lastname: Frazier
mesh_terms: D000483:Alleles; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001483:Base Sequence; D001549:Benzamides; D017326:Clinical Trials, Phase III as Topic; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005091:Exons; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000068877:Imatinib Mesylate; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D016032:Randomized Controlled Trials as Topic; D017154:Stromal Cells / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit