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Ref Type Journal Article
PMID (31205508)
Authors Liu F, Zou F, Chen C, Yu K, Liu X, Qi S, Wu J, Hu C, Hu Z, Liu J, Liu X, Wang L, Ge J, Wang W, Ren T, Bai M, Cai Y, Xiao X, Qian F, Tang J, Liu Q, Liu J
Title Axitinib overcomes multiple imatinib resistant cKIT mutations including the gatekeeper mutation T670I in gastrointestinal stromal tumors.
Journal Vol Issue Date Pages Journal Short Title
Therapeutic advances in medical oncology 11 2019 1758835919849757 Ther Adv Med Oncol
URL
Abstract Text cKIT kinase overexpression and gain-of-function mutations are the critical pathogenesis of gastrointestinal stromal tumors (GISTs). Although the multiple kinase inhibitors such as imatinib, sunitinib, and regorafenib have been approved for GISTs, the acquisition of polyclonal secondary resistance mutations in KIT is still a limitation for GIST treatment. Here we explored the KIT inhibitory activity of axitinib in preclinical models and describe initial characterization of its activity in GIST patient-derived primary cells.The activities of axitinib against mutant KIT were evaluated using protein-based assay and a panel of engineered and GIST-derived cell lines. The binding modes of axitinib-KIT/KIT mutants were analyzed. Four primary cells derived from GIST patients were also used to assess the drug response of axitinib.Axitinib exhibited potent activities against a variety of cKIT associated primary and secondary mutations. It displayed better activity against cKIT wild-type, cKIT V559D/A/G, and L576P primary gain-of-function mutations than imatinib, sunitinib, and regorafenib. In addition, it could inhibit imatinib resistant cKIT T670I and V654A mutants in vitro and in vivo GIST preclinical models.Our results provide the basis for extending the application of axitinib to GISTs patients who are unresponsive or intolerant to the current therapies.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT L576P Advanced Solid Tumor sensitive Axitinib Preclinical - Cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and proliferation of transformed cells expressing KIT L576P in culture (PMID: 31205508). 31205508
KIT V559G Advanced Solid Tumor sensitive Axitinib Preclinical - Cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and proliferation of transformed cells expressing KIT V559G in culture (PMID: 31205508). 31205508
KIT V560_Y578del KIT T670I gastrointestinal stromal tumor sensitive Axitinib Preclinical - Cell line xenograft Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and downstream signaling, reduced proliferation, and induced cell-cycle arrest in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT T670I in culture, and inhibited tumor growth in xenograft models (PMID: 31205508). 31205508
KIT T670I Advanced Solid Tumor sensitive Axitinib Preclinical - Cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and proliferation of transformed cells expressing KIT T670I in culture, however, with decreased potency compared to its potency against other KIT variants (PMID: 31205508). 31205508
KIT V654A Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT V654A in culture (PMID: 31205508). 31205508
KIT V654A Advanced Solid Tumor sensitive Axitinib Preclinical - Cell line xenograft Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and proliferation of transformed cells expressing KIT V654A in culture, and inhibited tumor growth in xenograft models (PMID: 31205508). 31205508
KIT V560_Y578del gastrointestinal stromal tumor sensitive Axitinib Preclinical - Cell line xenograft Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and downstream signaling, reduced proliferation and induced cell-cycle arrest in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture, and inhibited tumor growth in xenograft models (PMID: 31205508). 31205508
KIT V559D gastrointestinal stromal tumor sensitive Axitinib Preclinical - Patient cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited proliferation of gastrointestinal stromal tumor patient-derived primary cells harboring KIT V559D in culture (PMID: 31205508). 31205508
KIT K642E gastrointestinal stromal tumor sensitive Sunitinib Preclinical - Patient cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of a gastrointestinal stromal tumor (GIST) cell line and primary GIST patient-derived cells harboring KIT K642E in culture (PMID: 31205508). 31205508
KIT V560_Y578del KIT T670I gastrointestinal stromal tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT T670I in culture (PMID: 31205508). 31205508
KIT A829P Advanced Solid Tumor sensitive Axitinib Preclinical - Cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and proliferation of transformed cells expressing KIT A829P in culture, however, with decreased potency compared to its potency against other KIT variants (PMID: 31205508). 31205508
KIT V559D Advanced Solid Tumor sensitive Axitinib Preclinical - Cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and proliferation of transformed cells expressing KIT V559D in culture (PMID: 31205508). 31205508
KIT T670I Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT T670I in culture (PMID: 31205508). 31205508
KIT V559D KIT V654A Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT V654A and KIT V559D in culture (PMID: 31205508). 31205508
KIT V559A Advanced Solid Tumor sensitive Axitinib Preclinical - Cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and proliferation of transformed cells expressing KIT V559A in culture (PMID: 31205508). 31205508
KIT K642E gastrointestinal stromal tumor sensitive Axitinib Preclinical - Patient cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited phosphorylation of KIT and downstream signaling, reduced proliferation, and induced cell-cycle arrest in a cultured gastrointestinal stromal tumor (GIST) cell line harboring KIT K642E, and inhibited proliferation of primary GIST cells harboring KIT K642E in culture (PMID: 31205508). 31205508
KIT V559D KIT V654A Advanced Solid Tumor sensitive Axitinib Preclinical - Cell culture Actionable In a preclinical study, Inlyta (axitinib) inhibited KIT phosphorylation and proliferation of transformed cells expressing KIT V654A and KIT V559D in culture (PMID: 31205508). 31205508
KIT V559D KIT T670I Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT T670I and KIT V559D in culture (PMID: 31205508). 31205508
KIT V560_Y578del gastrointestinal stromal tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture (PMID: 31205508). 31205508