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Ref Type Journal Article
PMID (35194937)
Authors Liu J, Gao J, Wang A, Jiang Z, Qi S, Qi Z, Liu F, Yu K, Cao J, Chen C, Hu C, Wu H, Wang L, Wang W, Liu Q, Liu J
Title Nintedanib overcomes drug resistance from upregulation of FGFR signaling and imatinib-induced KIT mutations in gastrointestinal stromal tumors.
Journal Molecular oncology
Vol
Issue
Date 2022 Feb 23
URL
Abstract Text Drug resistance remains a major challenge in the clinical treatment of gastrointestinal stromal tumors (GISTs). While acquired on-target mutations of mast/stem cell growth factor receptor (KIT) kinase is the major resistance mechanism, activation of alternative signaling pathways may also play a role. Although several second- and third-generation KIT kinase inhibitors have been developed that could overcome some of the KIT mutations conferring resistance, the low clinical responses and narrow safety window have limited their broad application. The present study revealed that nintedanib not only overcame resistance induced by a panel of KIT primary and secondary mutations, but also overcame ERK-reactivation-mediated resistance caused by the upregulation of fibroblast growth factor (FGF) activity. In preclinical models of GISTs, nintedanib significantly inhibited the proliferation of imatinib-resistant cells, including GIST-5R, GIST-T1/T670I and GIST patient-derived primary cells. In addition, it also exhibited dose-dependent inhibition of ERK phosphorylation upon FGF ligand stimulation. In vivo antitumor activity was also observed in several xenograft GIST models. Considering the well-documented safety and pharmacokinetic (PK) profiles of nintedanib, this finding provides evidence for the repurposing of nintedanib as a new therapy for the treatment of GIST patients with de novo or acquired resistance to imatinib.

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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
KIT T670E missense unknown KIT T670E lies within the protein kinase domain of the Kit protein (UniProt.org). T670E has been identified in sequencing studies (PMID: 25886408, PMID: 19834613, PMID: 35194937), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Jul 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 V559D and T670I in culture (PMID: 35194937). 35194937
KIT V559D Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited proliferation of transformed cells expressing KIT V559D in culture (PMID: 35194937). 35194937
KIT V560_Y578del KIT T670I gastrointestinal stromal tumor sensitive Nintedanib Preclinical - Cell line xenograft Actionable In a preclinical study, Ofev (nintedanib) decreased Kit phosphorylation and downstream signaling, induced cell-cycle arrest and apoptosis, and inhibited proliferation of a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and T670I in culture, and suppressed tumor growth in cell line xenograft models (PMID: 35194937). 35194937
KIT V559G Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT V559D in culture (PMID: 35194937). 35194937
KIT V559G Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited proliferation of transformed cells expressing KIT V559G in culture (PMID: 35194937). 35194937
KIT D816V Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT D816V were resistant to Gleevec (imatinib) treatment in culture (PMID: 35194937). 35194937
KIT V559D KIT T670I Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V559D and T670I were resistant to Gleevec (imatinib) treatment in culture (PMID: 35194937). 35194937
KIT D820E Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited Kit autophosphorylation and proliferation of transformed cells expressing KIT D820E in culture (PMID: 35194937). 35194937
KIT V559D KIT V654A Advanced Solid Tumor resistant Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V559D and V654A were resistant to Ayvakit (avapritinib) treatment in culture (PMID: 35194937). 35194937
KIT T670I Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT T670I demonstrated resistance to Gleevec (imatinib) in culture (PMID: 35194937). 35194937
KIT V559D KIT V654A Advanced Solid Tumor predicted - sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V559D and V654A demonstrated decreased proliferation in response to Ofev (nintedanib) in culture, but were less sensitive to treatment compared to cells expressing either KIT V559D or KIT V654A alone (PMID: 35194937). 35194937
KIT V559D Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited Kit autophosphorylation and proliferation of transformed cells expressing KIT V559D in culture (PMID: 35194937). 35194937
KIT D820G Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited proliferation of transformed cells expressing KIT D820G in culture (PMID: 35194937). 35194937
KIT L576P Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT L576P in culture (PMID: 35194937). 35194937
KIT T670E Advanced Solid Tumor resistant Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT T670E demonstrated resistance to Ayvakit (avapritinib) in culture (PMID: 35194937). 35194937
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: 35194937). 35194937
KIT Y823D Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited Kit autophosphorylation and proliferation of transformed cells expressing KIT Y823D in culture (PMID: 35194937). 35194937
KIT T670I Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell line xenograft Actionable In a preclinical study, Ofev (nintedanib) inhibited Kit autophosphorylation and proliferation of transformed cells expressing KIT T670I in culture, and suppressed tumor growth in cell line xenograft models (PMID: 35194937). 35194937
KIT T670E Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT T670E in culture (PMID: 35194937). 35194937
KIT V559D KIT T670I Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited proliferation of transformed cells expressing KIT V559D and T670I in culture (PMID: 35194937). 35194937
KIT D816E Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited proliferation of transformed cells expressing KIT D816E in culture (PMID: 35194937). 35194937
KIT V559D KIT V654A Advanced Solid Tumor resistant Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V559D and V654A were resistant to Qinlock (ripretinib) treatment in culture (PMID: 35194937). 35194937
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: 35194937). 35194937
KIT V559D KIT T670I Advanced Solid Tumor resistant Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V559D and T670I were resistant to Ayvakit (avapritinib) treatment in culture (PMID: 35194937). 35194937
KIT L576P Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited Kit autophosphorylation and proliferation of transformed cells expressing KIT L576P in culture (PMID: 35194937). 35194937
KIT D816E Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT D816E in culture (PMID: 35194937). 35194937
KIT D816H Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT D816H were resistant to Gleevec (imatinib) treatment in culture (PMID: 35194937). 35194937
KIT K642E gastrointestinal stromal tumor sensitive Nintedanib Preclinical - Cell line xenograft Actionable In a preclinical study, Ofev (nintedanib) decreased Kit phosphorylation and downstream signaling, induced cell-cycle arrest and apoptosis, and inhibited proliferation of a gastrointestinal stromal tumor cell line and patient-derived cells harboring KIT K642E in culture, and suppressed tumor growth in cell line xenograft models (PMID: 35194937). 35194937
KIT T670E Advanced Solid Tumor resistant Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT T670E demonstrated resistance to Qinlock (ripretinib) in culture (PMID: 35194937). 35194937
KIT D820Y Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited proliferation of transformed cells expressing KIT D820Y in culture (PMID: 35194937). 35194937
KIT T670E Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT T670E demonstrated resistance to Gleevec (imatinib) in culture (PMID: 35194937). 35194937
KIT V654A Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited proliferation of transformed cells expressing KIT V654A in culture (PMID: 35194937). 35194937
KIT V559D gastrointestinal stromal tumor predicted - sensitive Nintedanib Preclinical - Patient cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited proliferation of patient-derived gastrointestinal stromal tumor cells harboring KIT V559D in culture (PMID: 35194937). 35194937
KIT L576P Advanced Solid Tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited proliferation of transformed cells expressing KIT L576P in culture (PMID: 35194937). 35194937
KIT V559G Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited Kit autophosphorylation and proliferation of transformed cells expressing KIT V559G in culture (PMID: 35194937). 35194937
KIT V560_Y578del gastrointestinal stromal tumor sensitive Nintedanib Preclinical - Cell line xenograft Actionable In a preclinical study, Ofev (nintedanib) decreased Kit phosphorylation and downstream signaling, induced cell-cycle arrest and apoptosis, and inhibited proliferation of a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture, and suppressed tumor growth in cell line xenograft models (PMID: 35194937). 35194937
KIT A829P Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited Kit autophosphorylation and proliferation of transformed cells expressing KIT A829P in culture (PMID: 35194937). 35194937
KIT V559D Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, Sutent (sunitinib) inhibited proliferation of transformed cells expressing KIT V559D in culture (PMID: 35194937). 35194937
KIT T670E Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited proliferation of transformed cells expressing KIT T670E in culture (PMID: 35194937). 35194937
KIT V559D KIT T670I Advanced Solid Tumor resistant Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V559D and T670I were resistant to Qinlock (ripretinib) treatment in culture (PMID: 35194937). 35194937
KIT D816E Advanced Solid Tumor sensitive Nintedanib Preclinical - Cell culture Actionable In a preclinical study, Ofev (nintedanib) inhibited proliferation of transformed cells expressing KIT D816E in culture (PMID: 35194937). 35194937
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 V559D and V654A in culture (PMID: 35194937). 35194937