RET G810 solvent front mutations may be one of the mechanisms behind resistance to selective RET inhibition with the drug selpercatinib, according to a recent study.
RET-specific tyrosine kinase inhibitors (TKIs) have shown efficacy against tumors, such as non-small cell lung cancer (NSCLC) or medullary thyroid cancer (MTC), that are positive for RET fusions or mutations. In some patients, RET mutation-mediated resistance to these drugs has been reported; however, the mechanisms of this resistance are unknown.
In this study, the researchers wanted to analyze circulating tumor DNA and tissue from patients who developed resistance after initial response to RET-specific TKI selpercatinib.
One of the included patients with KIF5B-RET NSCLC had a dramatic initial response to selpercatinib, but circulating tumor DNA analyses revealed emergence of RET G810R, G810S, and G810C mutations in the RET solvent front prior to resistance.
“Postmortem biopsy studies reported intratumor and intertumor heterogeneity with distinct disease subclones containing G810S, G810R, and G810C mutations in multiple disease sites indicative of convergent evolution on the G810 residue resulting in a common mechanism of resistance,” the researchers wrote.
Acquired mutations in RET G810 were also identified in another patient with CCDC6-RET fusion-positive NSCLC. Additionally, plasma from patients with RET fusion-positive NSCLC and RET-mutant MTC also showed acquired mutations in RET G810.
Acquired resistance was also modeled preclinically using CCDC6-RET fusion-positive NSCLC patient-derived xenografts. Four out of five animals treated with selpercatinib had tumor recurrence after initial response. Next-generation sequencing identified RET G810S mutations in 3 of the 4 recurrent tumors.
“Structural modeling predicted that these mutations sterically hinder the binding of selpercatinib, and in vitro assays confirmed loss of activity for both anti-RET multikinase inhibitors and selective RET TKIs,” the researchers wrote.
Solomon BJ, Tan L, Lin JJ, et al. RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies. J Thorac Oncol. 2020;15(4):541-549.