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Ref Type | Journal Article | ||||||||||||
PMID | (31085175) | ||||||||||||
Authors | Smith BD, Kaufman MD, Lu WP, Gupta A, Leary CB, Wise SC, Rutkoski TJ, Ahn YM, Al-Ani G, Bulfer SL, Caldwell TM, Chun L, Ensinger CL, Hood MM, McKinley A, Patt WC, Ruiz-Soto R, Su Y, Telikepalli H, Town A, Turner BA, Vogeti L, Vogeti S, Yates K, Janku F, Abdul Razak AR, Rosen O, Heinrich MC, Flynn DL | ||||||||||||
Title | Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants. | ||||||||||||
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Abstract Text | Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs. |
Molecular Profile | Treatment Approach |
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No data available in table |
Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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No data available in table |
Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Ripretinib | Ripretinib | 79 | 4 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Ripretinib | Qinlock | DCC-2618|DCC2618 | KIT Inhibitor 57 PDGFR-alpha Inhibitor 10 | Qinlock (ripretinib) is a dual inhibitor of KIT and PDGFRa, resulting in growth inhibition and anti-tumor effects (PMID: 29439183, PMID: 31085175, PMID: 31201392). Qinlock (ripretinib) is FDA approved for use in patients with advanced gastrointestinal stromal tumor who received 3 or more prior kinase inhibitor therapies (FDA.gov) |
Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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No data available in table |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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KIT V559_G565del KIT V654A KIT A829P | gastrointestinal stromal tumor | predicted - sensitive | Ripretinib | Case Reports/Case Series | Actionable | In a Phase I trial, treatment with Qinlock (ripretinib) decreased circulating tumor DNA, resulted in stable disease lasting over 26 months in a patient with gastrointestinal stromal tumor harboring a primary KIT V559_G565del mutation and two acquired resistance mutations, KIT V654A and KIT A829P (PMID: 31085175; NCT02571036). | 31085175 |
KIT Y568_L576delinsCV KIT D816E KIT D820Y | gastrointestinal stromal tumor | predicted - sensitive | Ripretinib | Case Reports/Case Series | Actionable | In a Phase I trial, treatment with Qinlock (ripretinib) decreased circulating tumor DNA, resulted in stable disease lasting over 21 months in a patient with gastrointestinal stromal tumor harboring a primary KIT Y568_L576delinsCV mutation and two acquired resistance mutations, KIT D816E and KIT D820Y (PMID: 31085175; NCT02571036). | 31085175 |
KIT W557_K558del KIT Y823D | gastrointestinal stromal tumor | sensitive | Ripretinib | Preclinical - Pdx | Actionable | In a preclinical study, Qinlock (ripretinib) induced tumor regression in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 31085175). | 31085175 |
KIT exon 11 del | gastrointestinal stromal tumor | sensitive | Ripretinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Qinlock (ripretinib) inhibited Kit phosphorylation and proliferation of gastrointestinal stromal tumor cells harboring KIT exon 11 deletion, resulted in tumor regression in cell line xenograft models (PMID: 31085175). | 31085175 |
KIT exon11 | gastrointestinal stromal tumor | sensitive | Ripretinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Qinlock (ripretinib) inhibited Kit phosphorylation and proliferation of gastrointestinal stromal tumor cells harboring a KIT exon 11 deletion mutation in culture, and resulted in tumor regression in cell line xenograft models (PMID: 31085175). | 31085175 |
KIT D816V | Advanced Solid Tumor | resistant | Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing KIT D816V were resistant to Stivarga (regorafenib) in culture (PMID: 31085175). | 31085175 |
KIT D816V | Advanced Solid Tumor | sensitive | Ripretinib | Preclinical - Cell culture | Actionable | In a preclinical study, Qinlock (ripretinib) inhibited proliferation of transformed cells expressing KIT D816V in culture (PMID: 31085175). | 31085175 |
KIT D816Y | mast cell neoplasm | decreased response | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, mouse mastocytoma cells harboring KIT D814Y (corresponds to D816Y in human) demonstrated reduced response to growth inhibition by Sutent (sunitinib) compared to GIST cells harboring KIT exon 11 deletion in culture (PMID: 31085175). | 31085175 |
KIT D816Y | mast cell neoplasm | predicted - resistant | Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, mouse mastocytoma cells harboring KIT D814Y (corresponds to D816Y in human) were resistant to Stivarga (regorafenib) in culture (PMID: 31085175). | 31085175 |
KIT D816Y | mast cell neoplasm | predicted - resistant | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, mouse mastocytoma cells harboring KIT D814Y (corresponds to D816Y in human) were resistant to Gleevec (imatinib) in culture (PMID: 31085175). | 31085175 |
KIT D816Y | mast cell neoplasm | predicted - sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited proliferation of mouse mastocytoma cells harboring KIT D814Y (corresponds to D816Y in human) in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del | gastrointestinal stromal tumor | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited Kit phosphorylation and proliferation of gastrointestinal stromal tumor cells harboring KIT exon 11 deletion in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del | gastrointestinal stromal tumor | sensitive | Avapritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Ayvakit (avapritinib) inhibited Kit phosphorylation and proliferation of gastrointestinal stromal tumor cells harboring KIT exon 11 deletion in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del | gastrointestinal stromal tumor | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) inhibited Kit phosphorylation and proliferation of gastrointestinal stromal tumor cells harboring KIT exon 11 deletion in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del | gastrointestinal stromal tumor | sensitive | Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Stivarga (regorafenib) inhibited Kit phosphorylation and proliferation of gastrointestinal stromal tumor cells harboring KIT exon 11 deletion in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del | gastrointestinal stromal tumor | predicted - sensitive | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Gleevec (imatinib) inhibited Kit phosphorylation and proliferation of gastrointestinal stromal tumor cells harboring KIT exon 11 deletion in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT D816E | gastrointestinal stromal tumor | resistant | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT D816E demonstrated reduced response to growth inhibition by Sutent (sunitinib) compared to cells harboring KIT exon 11 deletion alone in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT D816E | gastrointestinal stromal tumor | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT D816E in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT D816E | gastrointestinal stromal tumor | sensitive | Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Stivarga (regorafenib) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT D816E in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT D816E | gastrointestinal stromal tumor | sensitive | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Gleevec (imatinib) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT D816E in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT D816E | gastrointestinal stromal tumor | sensitive | Avapritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Ayvakit (avapritinib) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT D816E in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT D816E | gastrointestinal stromal tumor | sensitive | Ripretinib | Preclinical - Cell culture | Actionable | In a preclinical study, Qinlock (ripretinib) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT D816E in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT T670I | gastrointestinal stromal tumor | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT T670I in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT T670I | gastrointestinal stromal tumor | resistant | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT T670I were resistant to Gleevec (imatinib) in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT T670I | gastrointestinal stromal tumor | sensitive | Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Stivarga (regorafenib) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT T670I in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT T670I | gastrointestinal stromal tumor | sensitive | Avapritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Ayvakit (avapritinib) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT T670I in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT T670I | gastrointestinal stromal tumor | predicted - resistant | Ripretinib | Preclinical - Cell culture | Actionable | In a preclinical study, gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT T670I demonstrated reduced response to growth inhibition by Qinlock (ripretinib) compared to cells harboring KIT exon 11 deletion alone in culture (PMID: 31085175). | 31085175 |
KIT exon 11 del KIT T670I | gastrointestinal stromal tumor | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited proliferation of gastrointestinal stromal tumor cells harboring both KIT exon 11 deletion and KIT T670I in culture (PMID: 31085175). | 31085175 |
KIT N822K | acute myeloid leukemia | decreased response | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, acute myeloid leukemia cells harboring KIT N822K demonstrated reduced response to growth inhibition by Gleevec (imatinib) compared to GIST cells harboring KIT exon 11 deletion in culture (PMID: 31085175). | 31085175 |
KIT N822K | acute myeloid leukemia | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited proliferation of acute myeloid leukemia cells harboring KIT N822K in culture (PMID: 31085175). | 31085175 |
KIT N822K | acute myeloid leukemia | predicted - sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) inhibited proliferation of acute myeloid leukemia cells harboring KIT N822K in culture (PMID: 31085175). | 31085175 |
KIT N822K | acute myeloid leukemia | sensitive | Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Stivarga (regorafenib) inhibited proliferation of acute myeloid leukemia cells harboring KIT N822K in culture (PMID: 31085175). | 31085175 |
KIT N822K | acute myeloid leukemia | sensitive | Ripretinib | Preclinical - Cell culture | Actionable | In a preclinical study, Qinlock (ripretinib) inhibited proliferation of acute myeloid leukemia cells harboring KIT N822K in culture (PMID: 31085175). | 31085175 |
KIT V560G | mast cell neoplasm | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited proliferation of mast cells harboring KIT V560G in culture (PMID: 31085175). | 31085175 |
KIT V560G | mast cell neoplasm | sensitive | Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Stivarga (regorafenib) inhibited proliferation of mast cells harboring KIT V560G in culture (PMID: 31085175). | 31085175 |
KIT V560G | mast cell neoplasm | sensitive | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sutent (sunitinib) inhibited proliferation of mast cells harboring KIT V560G in culture (PMID: 31085175). | 31085175 |
KIT V560G | mast cell neoplasm | sensitive | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, Gleevec (imatinib) inhibited proliferation of mast cells harboring KIT V560G in culture (PMID: 31085175). | 31085175 |
KIT V560G | mast cell neoplasm | sensitive | Ripretinib | Preclinical - Cell culture | Actionable | In a preclinical study, Qinlock (ripretinib) inhibited proliferation of mast cells harboring KIT V560G in culture (PMID: 31085175). | 31085175 |
KIT V560G | mast cell neoplasm | sensitive | Avapritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Ayvakit (avapritinib) inhibited proliferation of mast cells harboring KIT V560G in culture (PMID: 31085175). | 31085175 |
KIT V560G KIT D816V | mast cell neoplasm | resistant | Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, mast cells harboring both KIT D816V and KIT V560G were resistant to Stivarga (regorafenib) in culture (PMID: 31085175). | 31085175 |
KIT V560G KIT D816V | mast cell neoplasm | sensitive | Avapritinib | Preclinical - Cell culture | Actionable | In a preclinical study, Ayvakit (avapritinib) inhibited proliferation of mast cells harboring KIT D816V and KIT V560G in culture (PMID: 31085175). | 31085175 |
KIT V560G KIT D816V | mast cell neoplasm | resistant | Imatinib | Preclinical - Cell culture | Actionable | In a preclinical study, mast cells harboring both KIT D816V and KIT V560G were resistant to Gleevec (imatinib) in culture (PMID: 31085175). | 31085175 |
KIT V560G KIT D816V | mast cell neoplasm | sensitive | Ripretinib | Preclinical - Cell culture | Actionable | In a preclinical study, Qinlock (ripretinib) inhibited proliferation of mast cells harboring KIT D816V and KIT V560G in culture, and inhibited tumor growth in cell line xenograft models (PMID: 31085175). | 31085175 |
KIT V560G KIT D816V | mast cell neoplasm | resistant | Sunitinib | Preclinical - Cell culture | Actionable | In a preclinical study, mast cells harboring both KIT D816V and KIT V560G were resistant to Sutent (sunitinib) in culture (PMID: 31085175). | 31085175 |
KIT V560G KIT D816V | mast cell neoplasm | sensitive | Midostaurin | Preclinical - Cell culture | Actionable | In a preclinical study, Rydapt (midostaurin) inhibited proliferation of mast cells harboring KIT D816V and KIT V560G in culture (PMID: 31085175). | 31085175 |
KIT D816Y | mast cell neoplasm | predicted - sensitive | Ripretinib | Preclinical | Actionable | In a preclinical study, Qinlock (ripretinib) inhibited proliferation of mouse mastocytoma cells harboring KIT D814Y (corresponds to D816Y in human) in culture, and resulted in tumor growth inhibition in allograft models (PMID: 31085175). | 31085175 |
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