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

César Serrano,César Serrano,César Serrano,César Serrano,Derrick L Tao,Jonathan A Fletcher,Aristotle M Mannan,Chandrajit P Raut,Channing Yu,Meijun Zhu,George D Demetri,Grant Eilers,Sebastian Bauer,Jonathan A Fletcher,George D Demetri,Suzanne George,Adrián Mariño-Enríquez,Adrián Mariño-Enríquez,Chandrajit P Raut,Jeffrey T Czaplinski,Brian P Rubin,Channing Yu,Ajia Presnell,Jonathan A Fletcher,Ewa Sicinska,Julia Ketzer,Derrick L Tao,Chandrajit P Raut,Arin Mckinley,Meijun Zhu,Grant Eilers,Michael C Heinrich,Channing Yu

doi:10.1038/s41416-019-0389-6

Abstract

BackgroundMost 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.MethodsWe 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.ResultsEach 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.ConclusionsOur 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.

Highlights

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
No substantial tyrosine kinase inhibitors (TKIs) effects were observed in KIT-independent GIST cell lines GIST48B and GIST226 (Table 1), which underscores that TKI-activity is typically mediated by blocking KIT signalling in imatinib-resistant GIST
These observations are consistent with previously reported clinicopathologic evidence that short-duration clinical responses in KIT-mutant GIST, after development of imatinib-resistance, result from outgrowth of cross-resistant GIST subpopulations with both ATP-binding pocket and activation loop KIT secondary mutations.[8,9,10,11]

Summary

Introduction

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. First-line imatinib mesylate (Gleevec, Novartis Oncology, Basel, Switzerland) inhibits activity of mutant KIT and PDGFRA, and substantially improves survival in most GIST patients.[6,7] most patients with initial clinical benefit from imatinib eventually progress, typically in 20–24 months.[6,7] Oncogenically-activated KIT continues to be the key driver of GIST proliferation and survival after imatinib failure in up to 90% of the patients, due to reactivation of KIT signalling by tumour subclones with heterogeneous secondary KIT mutations.[8,9,10,11] These KIT secondary mutations cluster in two regions of the kinase domain: the ATPbinding pocket (encoded by exons 13 and 14) and the activation loop (encoded by exons 17 and 18)

Methods

Results

Conclusion