Advancements in GIST Treatment: Exploring the Potential of DS-6157a, an Anti-GPR20 ADC

Gastrointestinal stromal tumors (GISTs) are predominantly driven by mutations in the KIT or PDGFRA genes, and tyrosine kinase inhibitors (TKIs) are the mainstay of treatment. However, resistance to these TKIs often arises, and they show limited efficacy in certain GIST subtypes. This calls for the development of alternative therapeutics. GPR20, an orphan G protein-coupled receptor, is selectively expressed in GIST and regulated by transcription factors involved in KIT-driven GIST, suggesting its potential as a therapeutic target.

In this study, the expression of GPR20 and KIT was assessed in GIST samples, revealing that GPR20 is present in over 88% of the samples analyzed. Notably, GPR20 expression was higher in treatment-experienced samples, those with higher KIT levels, small intestinal GISTs, and GISTs without KIT mutations, including SDH-deficient and NF1-associated GISTs. The interstitial cells of Cajal were identified as the only normal cells expressing GPR20.

DS-6157a, an antibody-drug conjugate (ADC) targeting GPR20, was developed and demonstrated GPR20-dependent inhibition of cell growth and tumor regression in multiple GIST xenograft models at doses ranging from 3 to 10 mg/kg. Importantly, DS-6157a showed antitumor activity in a patient-derived xenograft model resistant to standard TKIs, including imatinib, sunitinib, and regorafenib. The ADC induced markers of DNA damage and apoptosis in GPR20-expressing cells.

Preclinical toxicology studies in rats and cynomolgus monkeys showed a favorable safety profile for DS-6157a at doses up to 200 mg/kg and 30 mg/kg, respectively. These findings indicate the potential of DS-6157a as a novel therapy for GIST, particularly for patients who are resistant, refractory, or intolerant to approved TKIs.

This research was presented at the Annual Meeting of the American Association for Cancer Research in 2020, highlighting its significance in advancing GIST treatment options.