A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors.
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.
Chen
Lei L
LL
Department of Sarcoma, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. llchen@ mdanderson.org
Trent
Jonathan C
JC
Wu
Elsie F
EF
Fuller
Gregory N
GN
Ramdas
Latha
L
Zhang
Wei
W
Raymond
Austin K
AK
Prieto
Victor G
VG
Oyedeji
Caroline O
CO
Hunt
Kelly K
KK
Pollock
Raphael E
RE
Feig
Barry W
BW
Hayes
Kimberly J
KJ
Choi
Haesun
H
Macapinlac
Homer A
HA
Hittelman
Walter
W
Velasco
Marco A
MA
Patel
Shreyaskumar
S
Burgess
Michael A
MA
Benjamin
Robert S
RS
Frazier
Marsha L
ML
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
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit