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Ref Type Journal Article
PMID (32350132)
Authors Banks E, Grondine M, Bhavsar D, Barry E, Kettle JG, Reddy VP, Brown C, Wang H, Mettetal JT, Collins T, Adeyemi O, Overman R, Lawson D, Harmer AR, Reimer C, Drew L, Packer MJ, Cosulich S, Jones RD, Shao W, Wilson D, Guichard S, Fawell S, Anjum R
Title Discovery and pharmacological characterization of AZD3229, a potent KIT/PDGFRα inhibitor for treatment of gastrointestinal stromal tumors.
Journal Vol Issue Date Pages Journal Short Title
Science translational medicine 12 541 2020 Apr 29 Sci Transl Med
URL
Abstract Text Gastrointestinal stromal tumor (GIST) is the most common human sarcoma driven by mutations in KIT or platelet-derived growth factor α (PDGFRα). Although first-line treatment, imatinib, has revolutionized GIST treatment, drug resistance due to acquisition of secondary KIT/PDGFRα mutations develops in a majority of patients. Second- and third-line treatments, sunitinib and regorafenib, lack activity against a plethora of mutations in KIT/PDGFRα in GIST, with median time to disease progression of 4 to 6 months and inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) causing high-grade hypertension. Patients with GIST have an unmet need for a well-tolerated drug that robustly inhibits a range of KIT/PDGFRα mutations. Here, we report the discovery and pharmacological characterization of AZD3229, a potent and selective small-molecule inhibitor of KIT and PDGFRα designed to inhibit a broad range of primary and imatinib-resistant secondary mutations seen in GIST. In engineered and GIST-derived cell lines, AZD3229 is 15 to 60 times more potent than imatinib in inhibiting KIT primary mutations and has low nanomolar activity against a wide spectrum of secondary mutations. AZD3229 causes durable inhibition of KIT signaling in patient-derived xenograft (PDX) models of GIST, leading to tumor regressions at doses that showed no changes in arterial blood pressure (BP) in rat telemetry studies. AZD3229 has a superior potency and selectivity profile to standard of care (SoC) agents-imatinib, sunitinib, and regorafenib, as well as investigational agents, avapritinib (BLU-285) and ripretinib (DCC-2618). AZD3229 has the potential to be a best-in-class inhibitor for clinically relevant KIT/PDGFRα mutations in GIST.

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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
AZD3229 AZD3229 20 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
AZD3229 AZD-3229|AZD 3229 KIT Inhibitor 57 PDGFR-alpha Inhibitor 9 AZD3229 is an inhibitor of Kit and Pdgfra that may have anti-tumor activity against KIT/PDGFRA-driven tumors and may also be effective against acquired resistance mutations seen with other Kit/Pdgfra inhibitors (PMID: 32350132, PMID: 32220888).
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 W557_K558del KIT Y823D Advanced Solid Tumor predicted - sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated sensitivity to treatment with Stivarga (regorafenib), but was decreased compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT V654A demonstrated resistance to Stivarga (regorafenib) in culture (PMID: 32350132). 32350132
KIT V560D KIT D820A Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D820A demonstrated resistance to Sutent (sunitinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, Qinlock (ripretinib) treatment resulted in decreased viability of transformed cells expressing KIT W557_K558del in culture, but was less potent compared to treatment with AZD3229 (PMID: 32350132). 32350132
KIT V560D KIT V654A Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT V654A demonstrated sensitivity to Sutent (sunitinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT A502_Y503dup KIT D816H Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT D816H demonstrated resistance to Sutent (sunitinib) in culture (PMID: 32350132). 32350132
KIT A502_Y503dup KIT D816H Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT D816H demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT V560D KIT V654A Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT V654A demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT N822K Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT N822K demonstrated resistance to Sutent (sunitinib) in culture (PMID: 32350132). 32350132
KIT V560D KIT D820A Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D820A demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT D820A Advanced Solid Tumor conflicting Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT D820A were sensitive to treatment with Stivarga (regorafenib), demonstrating reduced cell viability in culture (PMID: 32350132). 32350132
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor resistant Imatinib Preclinical - Cell line xenograft Actionable In a preclinical study, Gleevec (imatinib) failed to decrease cell viability and KIT signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT V654A in culture, and did suppress tumor growth in cell line xenograft models (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive AZD3229 Preclinical - Pdx Actionable In a preclinical study, AZD3229 inhibited Kit signaling and tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 32350132). 32350132
KIT V560_Y578del gastrointestinal stromal tumor sensitive Imatinib Preclinical - Cell culture Actionable In a preclinical study, Gleevec (imatinib) inhibited cell growth and KIT signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture, but was less potent compared to AZD3229 (PMID: 32350132). 32350132
KIT W557_K558del KIT D820A Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT D820A demonstrated sensitivity to Qinlock (ripretinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor sensitive Sunitinib Preclinical - Cell line xenograft Actionable In a preclinical study, Sutent (sunitinib) inhibited growth of a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT V654A in culture, and inhibited tumor growth in cell line xenograft models (PMID: 32350132). 32350132
KIT A502_Y503dup KIT D816H Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT D816H demonstrated increased sensitivity to treatment with Ayvakit (avapritinib) compared to cells expressing KIT A502_Y503dup alone in culture (PMID: 32350132). 32350132
KIT A502_Y503dup KIT D816H Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT D816H demonstrated resistance to Stivarga (regorafenib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT A829P Advanced Solid Tumor conflicting Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT A829P were sensitive to treatment with Stivarga (regorafenib), but demonstrated a decreased response compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT V560_Y578del gastrointestinal stromal tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) inhibited cell growth and KIT signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture, but was less potent compared to AZD3229 (PMID: 32350132). 32350132
KIT W557_K558del KIT N822K Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT N822K demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D gastrointestinal stromal tumor sensitive Regorafenib Preclinical - Pdx Actionable In a preclinical study, Stivarga (regorafenib) inhibited tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT Y823D (PMID: 32350132). 32350132
KIT A502_Y503dup KIT D816H Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT D816H demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560D KIT D816H Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D816H demonstrated sensitivity to Qinlock (ripretinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560D KIT D820A Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D820A demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT D820A Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) treatment resulted in decreased viability of transformed cells expressing KIT W557_K558del and KIT D820A in culture, but was less effective compared to other treatments (PMID: 32350132). 32350132
KIT W557_K558del KIT D816H Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT D816H demonstrated sensitivity to Qinlock (ripretinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT A829P Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT A829P demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT V654A gastrointestinal stromal tumor sensitive Sunitinib Preclinical - Pdx Actionable In a preclinical study, Sutent (sunitinib) inhibited tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT V654A, which was established from a patient who did not respond to Gleevec (imatinib) treatment (PMID: 32350132). 32350132
KIT W557_K558del KIT V654A Advanced Solid Tumor resistant Ripretinib Preclinical - Cell culture Actionable In a preclinical study, Qinlock (ripretinib) failed to reduce cell viability and inhibit KIT signaling in transformed cells expressing KIT W557_K558del and KIT V654A in culture (PMID: 32350132). 32350132
KIT V560_Y578del gastrointestinal stromal tumor sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Stivarga (regorafenib) inhibited growth of a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture, but was less potent compared to AZD3229 (PMID: 32350132). 32350132
KIT V560D KIT V654A Advanced Solid Tumor decreased response Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT V654A demonstrated a decreased response to treatment with Qinlock (ripretinib) compared to cells expressing KIT V560D alone in culture (PMID: 32350132). 32350132
KIT A502_Y503dup Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability and inhibition of KIT signaling (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor decreased response Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated a decreased response to treatment with Qinlock (ripretinib) compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT A829P Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT A829P demonstrated sensitivity to Qinlock (ripretinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560D KIT D816H Advanced Solid Tumor decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D816H demonstrated a decreased response to treatment with Ayvakit (avapritinib) compared to cells expressing KIT V560D alone in culture (PMID: 32350132). 32350132
KIT K642E KIT N822K gastrointestinal stromal tumor sensitive Regorafenib Preclinical - Pdx Actionable In a preclinical study, Stivarga (regorafenib) suppressed tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT K642E and KIT N822K, but was less potent in comparison to treatment with AZD3229 (PMID: 32350132). 32350132
KIT A502_Y503dup Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, Qinlock (ripretinib) treatment resulted in decreased cell viability and reduced KIT signaling in transformed cells expressing KIT A502_Y503dup in culture, but was less potent compared to treatment with AZD3229 (PMID: 32350132). 32350132
KIT W557_K558del KIT A829P Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT A829P demonstrated resistance to Sutent (sunitinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT N822K Advanced Solid Tumor conflicting Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT N822K was sensitive to treatment with Stivarga (regorafenib), demonstrating decreased cell viability in culture (PMID: 32350132). 32350132
KIT A502_Y503dup KIT V654A Advanced Solid Tumor sensitive Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT V654A demonstrated sensitivity to Sutent (sunitinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT N822K Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) treatment resulted in decreased viability of transformed cells expressing KIT W557_K558del and KIT N822K in culture, but was less effective compared to other treatments (PMID: 32350132). 32350132
KIT W557_K558del KIT T670I Advanced Solid Tumor decreased response Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT T670I demonstrated a decreased response to treatment with Qinlock (ripretinib) compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT V560D KIT D816H Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D816H demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT D820A Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT D820A demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT V654A Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell line xenograft Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT V654A demonstrated sensitivity to treatment with AZD3229 in both culture and cell line xenograft models, resulting in reduced cell viability, decreased KIT signaling, and tumor regression (PMID: 32350132). 32350132
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor sensitive AZD3229 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD3229 suppressed Kit signaling and cell growth in culture, and inhibited tumor growth in a cell line xenograft model of gastrointestinal stromal tumor harboring KIT V560_Y578del and KIT V654A (PMID: 32350132). 32350132
KIT A502_Y503dup KIT V654A Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT V654A demonstrated resistance to Stivarga (regorafenib) in culture (PMID: 32350132). 32350132
KIT A502_Y503dup KIT V654A Advanced Solid Tumor resistant Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT V654A demonstrated resistance to Ayvakit (avapritinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT D816H Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT D816H demonstrated sensitivity to Ayvakit (avapritinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT A502_Y503dup KIT V654A Advanced Solid Tumor decreased response Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT V654A demonstrated a decreased response to treatment with Qinlock (ripretinib) compared to cells expressing KIT A502_Y503dup alone in culture (PMID: 32350132). 32350132
KIT W557_K558del Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) treatment resulted in decreased viability of transformed cells expressing KIT W557_K558del in culture, but was less potent compared to treatment with AZD3229 (PMID: 32350132). 32350132
KIT V560_Y578del gastrointestinal stromal tumor resistant Ripretinib Preclinical - Cell culture Actionable In a preclinical study, Qinlock (ripretinib) inhibited cell growth and KIT signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture, but was less potent compared to AZD3229 (PMID: 32350132). 32350132
KIT A502_Y503dup Advanced Solid Tumor sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Stivarga (regorafenib) treatment resulted in decreased viability of transformed cells expressing KIT A502_Y503dup in culture, but was less potent compared to treatment with AZD3229 (PMID: 32350132). 32350132
KIT V560D KIT D820A Advanced Solid Tumor sensitive Regorafenib Preclinical - Cell culture Actionable In a preclinical study, Stivarga (regorafenib) treatment resulted in decreased viability of transformed cells expressing KIT V560D and KIT D820A in culture, but was less effective compared to other treatments (PMID: 32350132). 32350132
KIT A502_Y503dup KIT D816H Advanced Solid Tumor decreased response Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT D816H demonstrated a decreased response to treatment with Qinlock (ripretinib) compared to cells expressing KIT A502_Y503dup alone in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT A829P Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) treatment resulted in decreased viability of transformed cells expressing KIT W557_K558del and KIT A829P in culture, but was less effective compared to other treatments (PMID: 32350132). 32350132
KIT W557_K558del KIT V654A gastrointestinal stromal tumor sensitive AZD3229 Preclinical - Pdx Actionable In a preclinical study, AZD3229 inhibited Kit signaling and tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_K558del and KIT V654A, which was established from a patient who did not respond to Gleevec (imatinib) treatment (PMID: 32350132). 32350132
KIT V560D KIT V654A Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT V654A demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT T670I Advanced Solid Tumor resistant Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT T670I demonstrated resistance to Ayvakit (avapritinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT N822K Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT N822K demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated resistance to Sutent (sunitinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT T670I Advanced Solid Tumor decreased response Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT T670I demonstrated a decreased response to treatment with Stivarga (regorafenib) compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT V560D Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) treatment resulted in decreased cell viability in transformed cells expressing KIT V560D in culture, but was less potent compared to treatment with AZD3229 (PMID: 32350132). 32350132
KIT V560D Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560D KIT D820A Advanced Solid Tumor decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D820A demonstrated a decreased response to treatment with Ayvakit (avapritinib) compared to cells expressing KIT V560D alone in culture (PMID: 32350132). 32350132
KIT V560D KIT V654A Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT V654A demonstrated resistance to treatment with Stivarga (regorafenib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT T670I Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT T670I demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT A829P Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT A829P demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560D KIT D816H Advanced Solid Tumor resistant Regorafenib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D816H demonstrated resistance to Stivarga (regorafenib) in culture (PMID: 32350132). 32350132
KIT A502_Y503dup KIT V654A Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT V654A demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560_Y578del gastrointestinal stromal tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, AZD3229 inhibited cell growth and KIT signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT Y823D Advanced Solid Tumor decreased response Avapritinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT Y823D demonstrated a decreased response to treatment with Ayvakit (avapritinib) compared to cells expressing KIT W557_K558del alone in culture (PMID: 32350132). 32350132
KIT K642E KIT N822K gastrointestinal stromal tumor sensitive AZD3229 Preclinical - Pdx Actionable In a preclinical study, AZD3229 inhibited Kit signaling and tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT K642E and KIT N822K (PMID: 32350132). 32350132
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor resistant Avapritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Ayvakit (avapritinib) failed to decrease cell viability and KIT signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT V654A in culture, and did suppress tumor growth in cell line xenograft models (PMID: 32350132). 32350132
KIT V560D KIT D816H Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D816H demonstrated resistance to Sutent (sunitinib) in culture (PMID: 32350132). 32350132
KIT V560D Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D demonstrated sensitivity to Qinlock (ripretinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT W557_K558del KIT D820A Advanced Solid Tumor resistant Sunitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT D820A demonstrated resistance to Sutent (sunitinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT D820A Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT D820A demonstrated sensitivity to AZD3229 in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT A502_Y503dup Advanced Solid Tumor sensitive Avapritinib Preclinical - Cell culture Actionable In a preclinical study, Ayvakit (avapritinib) treatment resulted in decreased cell viability and reduced KIT signaling in transformed cells expressing KIT A502_Y503dup in culture, but was less potent compared to treatment with AZD3229 (PMID: 32350132). 32350132
KIT W557_K558del KIT V654A Advanced Solid Tumor resistant Avapritinib Preclinical - Cell line xenograft Actionable In a preclinical study, Ayvakit (avapritinib) failed to inhibit cell growth or KIT signaling in culture and did not suppress tumor growth in cell line xenograft models of transformed cells expressing KIT W557_K558del and KIT V654A (PMID: 32350132). 32350132
KIT W557_K558del KIT N822K Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT W557_K558del and KIT N822K demonstrated sensitivity to Qinlock (ripretinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132
KIT V560D KIT D816H Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D816H demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT W557_K558del KIT D816H Advanced Solid Tumor sensitive AZD3229 Preclinical - Cell line xenograft Actionable In a preclinical study, AZD3229 inhibited growth of cells in culture and tumor growth in a cell line xenograft model of transformed cells expressing KIT W557_K558del and KIT D816H (PMID: 32350132). 32350132
KIT V560_Y578del KIT V654A gastrointestinal stromal tumor predicted - resistant Ripretinib Preclinical - Cell line xenograft Actionable In a preclinical study, Qinlock (ripretinib) resulted in slight decreases in cell viability and KIT signaling in a gastrointestinal stromal tumor cell line harboring KIT V560_Y578del and KIT V654A in culture, but failed to suppress tumor growth in cell line xenograft models (PMID: 32350132). 32350132
KIT A502_Y503dup KIT V654A Advanced Solid Tumor resistant Imatinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT A502_Y503dup and KIT V654A demonstrated resistance to Gleevec (imatinib) in culture (PMID: 32350132). 32350132
KIT V560D KIT D820A Advanced Solid Tumor sensitive Ripretinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing KIT V560D and KIT D820A demonstrated sensitivity to Qinlock (ripretinib) in culture, resulting in reduced cell viability (PMID: 32350132). 32350132