Molecular correlates of imatinib resistance in gastrointestinal stromal tumors.
OBJECTIVE
Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT or platelet-derived growth factor alpha (PDGFRA) kinases, which are targets for imatinib. In clinical studies, 75% to 90% of patients with advanced GISTs experience clinical benefit from imatinib. However, imatinib resistance is an increasing clinical problem.


METHODS
One hundred forty-seven patients with advanced, unresectable GISTs were enrolled onto a randomized, phase II clinical study of imatinib. Specimens from pretreatment and/or imatinib-resistant tumors were analyzed to identify molecular correlates of imatinib resistance. Secondary kinase mutations of KIT or PDGFRA that were identified in imatinib-resistant GISTs were biochemically profiled for imatinib sensitivity.


RESULTS
Molecular studies were performed using specimens from 10 patients with primary and 33 patients with secondary resistance. Imatinib-resistant tumors had levels of activated KIT that were similar to or greater than those typically found in untreated GISTs. Secondary kinase mutations were rare in GISTs with primary resistance but frequently found in GISTs with secondary resistance (10% v 67%; P = .002). Evidence for clonal evolution and/or polyclonal secondary kinase mutations was seen in three (18.8%) of 16 patients. Secondary kinase mutations were nonrandomly distributed and were associated with decreased imatinib sensitivity compared with typical KIT exon 11 mutations. Using RNAi technology, we demonstrated that imatinib-resistant GIST cells remain dependent on KIT kinase activity for activation of critical downstream signaling pathways.


CONCLUSIONS
Different molecular mechanisms are responsible for primary and secondary imatinib resistance in GISTs. These findings have implications for future approaches to the growing problem of imatinib resistance in patients with advanced GISTs.
Heinrich
Michael C
MC
Division of Hematology/Oncology, Department of Pathology, Oregon Health & Science University Cancer Institute, Oregon Health & Science University, Portland, OR, USA. Heinrich@ohsu.edu
Corless
Christopher L
CL
Blanke
Charles D
CD
Demetri
George D
GD
Joensuu
Heikki
H
Roberts
Peter J
PJ
Eisenberg
Burton L
BL
von Mehren
Margaret
M
Fletcher
Christopher D M
CD
Sandau
Katrin
K
McDougall
Karen
K
Ou
Wen-bin
WB
Chen
Chang-Jie
CJ
Fletcher
Jonathan A
JA
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D010879:Piperazines / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; C075278:platelet-derived growth factor A; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit