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

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

    Research output: Contribution to journalArticle

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    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.

    Original languageEnglish (US)
    Pages (from-to)612-620
    Number of pages9
    JournalBritish Journal of Cancer
    Volume120
    Issue number6
    DOIs
    StatePublished - Mar 19 2019

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    Gastrointestinal Stromal Tumors
    Protein-Tyrosine Kinases
    Mutation
    Clinical Trials
    Growth
    Imatinib Mesylate
    Adenosine Triphosphate
    sunitinib
    regorafenib
    Therapeutics

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. / Serrano, César; Mariño-Enríquez, Adrián; Tao, Derrick L.; Ketzer, Julia; Eilers, Grant; Zhu, Meijun; Yu, Channing; Mannan, Aristotle M.; Rubin, Brian P.; Demetri, George D.; Raut, Chandrajit P.; Presnell, Ajia; McKinley, Arin; Heinrich, Michael; Czaplinski, Jeffrey T.; Sicinska, Ewa; Bauer, Sebastian; George, Suzanne; Fletcher, Jonathan A.

    In: British Journal of Cancer, Vol. 120, No. 6, 19.03.2019, p. 612-620.

    Research output: Contribution to journalArticle

    Serrano, C, Mariño-Enríquez, A, Tao, DL, Ketzer, J, Eilers, G, Zhu, M, Yu, C, Mannan, AM, Rubin, BP, Demetri, GD, Raut, CP, Presnell, A, McKinley, A, Heinrich, M, Czaplinski, JT, Sicinska, E, Bauer, S, George, S & Fletcher, JA 2019, 'Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours' British Journal of Cancer, vol. 120, no. 6, pp. 612-620. https://doi.org/10.1038/s41416-019-0389-6
    Serrano, César ; Mariño-Enríquez, Adrián ; Tao, Derrick L. ; Ketzer, Julia ; Eilers, Grant ; Zhu, Meijun ; Yu, Channing ; Mannan, Aristotle M. ; Rubin, Brian P. ; Demetri, George D. ; Raut, Chandrajit P. ; Presnell, Ajia ; McKinley, Arin ; Heinrich, Michael ; Czaplinski, Jeffrey T. ; Sicinska, Ewa ; Bauer, Sebastian ; George, Suzanne ; Fletcher, Jonathan A. / Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours. In: British Journal of Cancer. 2019 ; Vol. 120, No. 6. pp. 612-620.
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    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.",
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    T1 - Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours

    AU - Serrano, César

    AU - Mariño-Enríquez, Adrián

    AU - Tao, Derrick L.

    AU - Ketzer, Julia

    AU - Eilers, Grant

    AU - Zhu, Meijun

    AU - Yu, Channing

    AU - Mannan, Aristotle M.

    AU - Rubin, Brian P.

    AU - Demetri, George D.

    AU - Raut, Chandrajit P.

    AU - Presnell, Ajia

    AU - McKinley, Arin

    AU - Heinrich, Michael

    AU - Czaplinski, Jeffrey T.

    AU - Sicinska, Ewa

    AU - Bauer, Sebastian

    AU - George, Suzanne

    AU - Fletcher, Jonathan A.

    PY - 2019/3/19

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    N2 - 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.

    AB - 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.

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