Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Cancer discovery	11	6	2021 Jun	1508-1523	Cancer Discov

URL

Abstract Text

Currently, the only approved treatments for gastrointestinal stromal tumor (GIST) are tyrosine kinase inhibitors (TKI), which eventually lead to the 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-tyrosine kinase target in GIST, developed new GPR20 IHC, and assessed GPR20 expression in cell lines, patient-derived xenografts, and clinical samples from two institutes (United States and 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. Preclinical pharmacokinetics and safety profile of DS-6157a support its clinical development as a potential novel GIST therapy in patients who are refractory or have resistance or intolerance to approved TKIs. SIGNIFICANCE: GPR20 is selectively expressed in GIST across all treatment lines, regardless of KIT / PDGFRA genotypes. We generated DS-6157a, a DXd-based antibody-drug conjugate that exhibited antitumor activity in GIST models by a different mode of action than currently approved TKIs, showing favorable pharmacokinetics and safety profiles. This article is highlighted in the In This Issue feature, p. 1307 .

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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
DS-6157a	DS-6157a	0	1

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, Nov 2024).

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