Ponatinib Inhibits Polyclonal Drug-Resistant KIT Oncoproteins and Shows Therapeutic Potential in Heavily Pretreated Gastrointestinal Stromal Tumor (GIST) Patients

Abstract

Purpose KIT is the major oncogenic driver of gastrointestinal stromal tumors (GISTs). Imatinib, sunitinib and regorafenib are approved therapies; however, efficacy is often limited by the acquisition of polyclonal secondary resistance mutations in KIT, with those located in the activation (A) loop (exons 17/18) being particularly problematic. Here we explored the KIT inhibitory activity of ponatinib in preclinical models and describe initial characterization of its activity in GIST patients. Experimental Design The cellular and in vivo activities of ponatinib, imatinib, sunitinib and regorafenib against mutant KIT were evaluated using an accelerated mutagenesis assay and a panel of engineered and GIST-derived cell lines. The ponatinib-KIT co-structure was also determined. The clinical activity of ponatinib was examined in three GIST patients previously treated with all 3 FDA-approved agents. Results In engineered and GIST-derived cell lines, ponatinib potently inhibited KIT exon 11 primary mutants and a range of secondary mutants, including those within the A-loop. Ponatinib also induced regression in engineered and GIST-derived tumor models containing these secondary mutations. In a mutagenesis screen, 40 nM ponatinib was sufficient to suppress outgrowth of all secondary mutants except V654A, which was suppressed at 80 nM. This inhibitory profile could be rationalized based on structural analyses. Ponatinib (30 mg daily) displayed encouraging clinical activity in two of three GIST patients. Conclusion Ponatinib possesses potent activity against most major clinically-relevant KIT mutants, and has demonstrated preliminary evidence of activity in patients with refractory GIST. These data strongly support further evaluation of ponatinib in GIST patients.

Gastrointestinale Stromatumoren (GIST) – Neues zu Pathologie, Chirurgie und medikamentöser Therapie

“…Regorafenib ist ein Multikinaseinhibitor von Proteinkinasen, die an Tumorangiogenese (VEGFR-1, -2, and -3, and TIE2), Onkogenese (KIT, RET, RAF-1, BRAF, und BRAFV600E) und dem Tumormikroenvironment (PDGFR und FGFR) beteiligt sind [52]. [54].…”

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

“…It was shown to significantly inhibit tumor growth in in vitro and in vivo models of glioblastoma multiforme [73] and acute myeloid leukemia [74]. To elucidate the in vitro and in vivo efficacy of ponatinib, Garner and colleagues assessed the drug across a panel of GIST cell lines derived from patients with varying mutational statuses [75]. They demonstrated that ponatinib was highly active in lines containing KIT exon 11 mutation and an array of secondary mutations, including activation loop and T670I gatekeeper mutations, but not V654A secondary mutation.…”

State of the Art in the Treatment of Gastrointestinal Stromal Tumors

“…Among novel multikinase inhibitors, ponatinib might have the potential to become a new treatment option for patients refractory to all known TKIs. Ponatinib has demonstrated in vitro activity against a number of clinically relevant KIT mutants [88]. In a phase II study of 35 patients with refractory metastatic GISTs, roughly 50% of whom had progressed on all three established TKIs, ponatinib achieved response or disease stabilization in 55% of patients with and 22% of patients without a primary KIT exon 11 mutation [89].…”