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

British Journal of Cancer
César SerranoJ A Fletcher

Abstract

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. 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. 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. Our data highlight that heterogeneity of KIT secondary mutations is the ...Continue Reading

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Citations

Feb 23, 2019·British Journal of Cancer·Andrea Napolitano, Bruno Vincenzi
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Jul 1, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·César Serrano, Suzanne George
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Jan 22, 2021·Therapeutic Advances in Medical Oncology·M Julia Lostes-BardajiCésar Serrano
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Mar 2, 2021·Expert Opinion on Emerging Drugs·Daniel F Pilco-JanetaCésar Serrano
Mar 1, 2021·Current Treatment Options in Oncology·David Gómez-PeregrinaCésar Serrano
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Sep 11, 2021·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sebastian BauerPatrick Schöffski
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Methods Mentioned

BETA
protein assay
xenograft
biopsies
biopsy

Clinical Trials Mentioned

NCT02164240

Software Mentioned

PRISM

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