Targeting RET Mutations: The Promise of DS-5010 in Cancer Therapy

The study explores the role of RET gene rearrangement in various cancers, such as non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma, where it acts as a driver mutation. Despite FDA-approved multi-tyrosine kinase inhibitors (MTKIs) demonstrating inhibitory effects on RET kinase activity, they have not shown significant clinical benefits due to dose-limiting toxicity (DLT), particularly with hypertension linked to Kinase insert domain receptor (KDR) inhibition. The development of more potent and selective second-generation RET inhibitors is therefore necessary.

DS-5010, a novel oral small-molecule RET inhibitor, has been found to be highly potent and specific against RET and gatekeeper-mutated RET (RET-GKm), with minimal KDR activity. In vitro assays revealed that DS-5010 significantly inhibits RET and platelet-derived growth factor receptor (PDGFR) alpha/beta at low concentrations, with a half-maximal inhibitory concentration (IC50) in the single-digit nano-molar range for RET and RET-GKm, even in the presence of high ATP levels. In contrast, its IC50 against KDR was substantially higher.

In vivo models demonstrated DS-5010's effectiveness in inducing tumor regression at specific dosages, unlike FDA-approved MTKIs which showed no significant antitumor effect in a model with RET-GKm mutation. Furthermore, DS-5010 was effective in an NSCLC xenograft model with the RET-CCDC6 fusion gene.

Resistance to FDA-approved MTKIs was addressed by establishing resistant clones through prolonged exposure to cabozantinib, which all possessed the V804E mutation in the RET kinase domain. DS-5010 was able to inhibit the proliferation of these resistant clones effectively, whereas FDA-approved MTKIs showed weak inhibitory effects.

The study concludes that DS-5010 exhibits strong in vitro and in vivo activities against RET and RET-GKm mutations, suggesting its potential as a targeted therapy for cancers with RET gene rearrangements. It also shows promise in combating MTKI-resistant cells. Investigational new drug-enabling studies for DS-5010 are currently underway.

Reference: Kaneta Y, Komatsu T, Miyamoto M, et al. Preclinical characterization and antitumor efficacy of DS-5010, a highly potent and selective RET inhibitor [abstract]. Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B173.