Targeting RET Mutations: The Emergence of TAS0953/HM06 as a Potent Inhibitor

The abstract discusses the role of RET gene fusions in various cancers, particularly in 1-2% of non-squamous non-small cell lung cancers (NSCLCs). It highlights the limitations of first-generation RET inhibitors, selpercatinib and pralsetinib, which have faced challenges due to acquired resistances from mutations like G810R/S/C. TAS0953/HM06, a new, highly selective RET inhibitor, is presented as a potential solution to overcome these resistances.

A panel test involving 254 kinases showed that TAS0953/HM06 selectively inhibits RET at 23 nM, with a similar potency to selpercatinib and pralsetinib against wild-type (WT) RET. The inhibitor was effective against engineered cells with RET WT fusions and mutations, including the resistant mutations G810R/S and gatekeeper mutations V804L/M.

Crystal structure analysis revealed that TAS0953/HM06 has a unique binding mode to RET, avoiding the steric hindrance caused by solvent front substitutions, which is likely why it maintains its potency against G810 mutations.

In vivo testing in a xenograft tumor model using mice showed that TAS0953/HM06, even at a low dose of 10 mg/kg twice daily, significantly inhibited tumor growth and phospho-RET. The study suggests that TAS0953/HM06 is not only potent against WT RET but also effective against the G810R mutation, which is resistant to first-generation inhibitors.

The abstract concludes that TAS0953/HM06 could be a new therapeutic option for patients with RET mutations, including those resistant to first-generation inhibitors. The compound is currently under investigation in a phase 1/2 clinical trial (NCT04683250). The citation is for Isao Miyazaki et al., presenting their findings at the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics in October 2021.