Reference Detail

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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

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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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Showing 1 to 19 of 19 entries

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
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 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 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 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 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 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 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 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 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 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 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 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 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 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 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 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	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
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 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

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