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Published on: March 28, 2021
Identification and Therapeutic Targeting of GPR20, Selectively Expressed in Gastrointestinal Stromal Tumors, with
Kenji Iida1, Amr H Abdelhamid Ahmed2,3,4, Akiko Kawano Nagatsuma5
1Daiichi Sankyo, Co., Ltd., Tokyo, Japan. iida.kenji.ve@daiichisankyo.co.jp.
Abstract:
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.
Insights
Researchers identified G protein-coupled receptor 20 (GPR20) as a new target for gastrointestinal stromal tumor (GIST). They developed DS-6157a, an antibody-drug conjugate, showing promise against GIST resistant to current therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Gastrointestinal stromal tumor (GIST) treatments, primarily tyrosine kinase inhibitors (TKIs), face challenges due to secondary resistance mutations.
- Novel therapeutic targets beyond KIT and PDGFRA are needed for GIST management.
Purpose of the Study:
- To identify and validate G protein-coupled receptor 20 (GPR20) as a novel non-TKI target in GIST.
- To develop and evaluate DS-6157a, an anti-GPR20 antibody-drug conjugate (ADC), for GIST treatment.
Main Methods:
- GPR20 expression was assessed using immunohistochemistry (IHC) in GIST cell lines, patient-derived xenografts, and clinical samples.
- DS-6157a, an ADC comprising an anti-GPR20 antibody and a DNA topoisomerase I inhibitor (DXd), was developed.
- Antitumor activity of DS-6157a was evaluated in GIST xenograft models, including those resistant to established TKIs.
Main Results:
- GPR20 was found to be selectively expressed in GIST across various treatment lines and molecular subtypes, independent of KIT/PDGFRA mutations.
- DS-6157a demonstrated GPR20-dependent antitumor efficacy in preclinical GIST models, including TKI-resistant settings.
- DS-6157a exhibited favorable preclinical pharmacokinetics and safety profiles, supporting its clinical development.
Conclusions:
- GPR20 represents a promising novel therapeutic target for GIST.
- DS-6157a, a GPR20-targeted ADC, offers a new treatment modality for GIST patients refractory or resistant to approved TKIs.
