Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours

Abstract

BACKGROUND: Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration. METHODS:We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity. RESULTS: Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy. CONCLUSIONS: Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells

“…imatinib. Although preliminary results from our laboratory exploring a combination of imatinib and bortezomib did not show clear synergistic effects, alternative administration regimens, such as drug sequencing, could be explored 44 . Combinations with other agents might also be promising.…”

Intrigue: Phase III Study of Ripretinib Versus Sunitinib in Advanced Gastrointestinal Stromal Tumor After Imatinib

“…Both preclinical and correlative clinical studies suggest that secondary resistance mutations of KIT in exon 17 (with the exception of the D816 substitutions) are inhibited. However, in contrast to results with sunitinib, exons 13 and 14 mutations are associated with resistance [47,52,57]. Attempts to use the complementary inhibitory profiles of sunitinib and regorafenib that were promising in vitro have been problematic in clinical trials due to the additive toxicity [57,58].…”

“…However, in contrast to results with sunitinib, exons 13 and 14 mutations are associated with resistance [47,52,57]. Attempts to use the complementary inhibitory profiles of sunitinib and regorafenib that were promising in vitro have been problematic in clinical trials due to the additive toxicity [57,58]. No other approved treatment options exist after the approved third-line agent to treat these patients.…”

Differential antitumor activity of compounds targeting the ubiquitin-proteasome machinery in gastrointestinal stromal tumor (GIST) cells

“…imatinib. Although preliminary results from our laboratory exploring a combination of imatinib and bortezomib did not show clear synergistic effects, alternative administration regimens, such as drug sequencing, could be explored 43 . Combinations with other agents than imatinib might also be promising.…”