To realize the full potential of targeted
protein kinase inhibitors for the treatment of
cancer, it is important to address the emergence of drug resistance in treated patients. Mutant forms of BCR-ABL, KIT, and the
EGF receptor (EGFR) have been found that confer resistance to the drugs
imatinib,
gefitinib, and
erlotinib. The mutations weaken or prevent
drug binding, and interestingly, one of the most common sites of mutation in all three
kinases is a highly conserved "gatekeeper"
threonine residue near the
kinase active site. We have identified existing clinical compounds that bind and inhibit
drug-resistant mutant variants of ABL, KIT, and EGFR. We found that the
Aurora kinase inhibitor
VX-680 and the p38 inhibitor
BIRB-796 inhibit the
imatinib- and BMS-354825-resistant ABL(T315I)
kinase. The KIT/FLT3 inhibitor
SU-11248 potently inhibits the
imatinib-resistant KIT(V559D/T670I)
kinase, consistent with the clinical efficacy of
SU-11248 against
imatinib-resistant gastrointestinal
tumors, and the EGFR inhibitors
EKB-569 and
CI-1033, but not
GW-572016 and
ZD-6474, potently inhibit the
gefitinib- and
erlotinib-resistant EGFR(L858R/T790M)
kinase.
EKB-569 and
CI-1033 are already in clinical trials, and our results suggest that they should be considered for testing in the treatment of
gefitinib/
erlotinib-resistant
non-small cell lung cancer. The results highlight the strategy of screening existing clinical compounds against newly identified
drug-resistant mutant variants to find compounds that may serve as starting points for the development of next-generation drugs, or that could be used directly to treat patients that have acquired resistance to first-generation targeted
therapy.