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Ref Type Journal Article
PMID (33579785)
Authors Iida K, Abdelhamid Ahmed AH, Nagatsuma AK, Shibutani T, Yasuda S, Kitamura M, Hattori C, Abe M, Hasegawa J, Iguchi T, Karibe T, Nakada T, Inaki K, Kamei R, Abe Y, Nomura T, Andersen JL, Santagata S, Hemming ML, George S, Doi T, Ochiai A, Demetri GD, Agatsuma T
Title Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with DS-6157a, a First-In-Class Antibody-Drug Conjugate.
Journal Cancer discovery
Vol
Issue
Date 2021 Feb 12
URL
Abstract Text Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKIs), which eventually lead to development of secondary resistance mutations in KIT or PDGFRA and disease progression. Herein, we identified G protein-coupled receptor 20 (GPR20) as a novel non-TK target in GIST, developed new GPR20 immunohistochemistry, assessed GPR20 expression in cell lines, PDXs & clinical samples from 2 institutes (USA & Japan). We studied GPR20 expression stratified by treatment line; KIT expression; GIST molecular subtype; and primary tumor location. We produced DS-6157a, an anti-GPR20 antibody-drug conjugate with a novel tetrapeptide-based linker and DNA topoisomerase I inhibitor exatecan-derivative (DXd). DS-6157a exhibited GPR20 expression-dependent antitumor activity in GIST xenograft models including a GIST model resistant to imatinib, sunitinib, and regorafenib. Pre-clinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients with resistance, refractory, or intolerance to approved TKIs.

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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
DS-6157a DS 6157a|DS6157a DS-6157a is an antibody-drug conjugate (ADC) comprising an antibody that targets GPR20 linked to DXd, a DNA topoisomerase I inhibitor, which may inhibit tumor growth (PMID: 33579785).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
KIT A755T missense unknown KIT A755T lies within the protein kinase domain of the Kit protein (UniProt.org). A755T has been identified in the scientific literature (PMID: 33579785, PMID: 27023146), but has not been biochemically characterized and therefore, its effect on Kit protein function is unknown (PubMed, Jun 2022).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
KIT W557_E561del gastrointestinal stromal tumor sensitive Imatinib Preclinical - Pdx Actionable In a preclinical study, Gleevec (imatinib) inhibited tumor growth in a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT W557_E561del with overexpression of GPR20 (IHC score 3+) (PMID: 33579785). 33579785
KIT W557_E561del 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_E561del with overexpression of GPR20 (IHC score 3+) (PMID: 33579785). 33579785
KIT V560_L576del KIT V654A 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 V560_L576del and V654A with overexpression of GPR20 (IHC score 3+) (PMID: 33579785). 33579785
KIT V560_L576del 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 V560_L576del and V654A with overexpression of GPR20 (IHC score 3+) (PMID: 33579785). 33579785
KIT V560_L576del KIT V654A gastrointestinal stromal tumor resistant Imatinib Preclinical - Pdx Actionable In a preclinical study, a patient-derived xenograft (PDX) model of gastrointestinal stromal tumor harboring KIT V560_L576del and V654A with overexpression of GPR20 (IHC score 3+) demonstrated resistance to treatment with Gleevec (imatinib) (PMID: 33579785). 33579785