The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors;: kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations

Mutations of c-KIT causing spontaneous activation of the KIT receptor kinase are associated with sporadic adult human mastocytosis (SAHM) and with human gastrointestinal stromal tumors. We have classified KIT-activating mutations as either "enzymatic site" type (EST) mutations, affecting the structure of the catalytic portion of the kinase, or as "regulatory" type (FIT) mutations, affecting regulation of an otherwise normal catalytic site. Using COS cells expressing wild-type or mutant KIT, 2 compounds, STI571 and SU9529, Inhibited wild-type and RT mutant KIT at 0.1 to 1 muM but did not significantly inhibit the Asp816VaI EST mutant associated with SAHM, even at 10 muM. Using 2 subclones of the HMC1 mast cell line, which both express KIT with an identical FIT mutation but which differ in that one also expresses the Asp816VaI EST mutation, both compounds inhibited the RT mutant KIT, thereby suppressing proliferation and producing apoptosis in the FIT mutant-only cell line. Neither compound suppressed activation of Asp816VaI EST mutant KIT, and neither produced apoptosis or significantly suppressed proliferation of the cell line expressing the Asp816VaI mutation. These studies suggest that currently available KIT inhibitors may be useful in treating neoplastic cells expressing KIT activated by its. natural ligand or by FIT activating mutations such as gastrointestinal stromal tumors but that neither compound is likely to be effective against SAHM. Furthermore, these results help establish a general, paradigm whereby classification of mutations affecting oncogenic enzymes as RT or EST may be useful in predicting tumor sensitivity or resistance to inhibitory drugs.