Chasing the Target: New Phenomena of Resistance to Novel Selective RET Inhibitors in Lung Cancer. Updated Evidence and Future Perspectives

Abstract

The potent, RET-selective tyrosine kinase inhibitors (TKIs) pralsetinib and selpercatinib, are effective against the RET V804L/M gatekeeper mutants, however, adaptive mutations that cause resistance at the solvent front RET G810 residue have been found, pointing to the need for the development of the next-generation of RET-specific TKIs. Also, as seen in EGFR- and ALK-driven NSCLC, the rising of the co-occurring amplifications of KRAS and MET could represent other escaping mechanisms from direct inhibition. In this review, we summarize actual knowledge on RET fusions, focusing on those involved in NSCLC, the results of main clinical trials of approved RET-inhibition drugs, with particular attention on recent published results of selective TKIs, and finally, pre-clinical evidence regarding resistance mechanisms and suggestion on hypothetical and feasible drugs combinations and strategies viable in the near future.

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“…Recently, two patients with nonsmall cell lung cancer (NSCLC), extensively pretreated with chemotherapy and MKIs and having an initial response to selpercatinib, finally developed resistance to this drug. Structural and functional studies in tumor tissue showed that the most likely mechanism was the occurrence of acquired RET solvent front mutations, resulting in interference of the mutated residue with drug-target binding [65,66 ]. Moreover, in-vitro studies confirmed that cabozantinib, vandetanib, selpercatinib and pralsetinib all lost inhibitory effect against nongatekeeper mutations RET G810S, G810R and G810C, whereas for selpercatinib and pralsetinib the inhibitor activity against RET V804and S904F gatekeeper mutations was maintained [65].…”

Research Progress on RET Fusion in Non-Small-Cell Lung Cancer

“…Pralsetinib was the second selective RET inhibitor with highly potent and selective for wild-type RET, RET fusion (including the most common KIF5B-RET and CCDC6-RET), and mutations (RET V804 L, RET V804 M, and RET M918T) ( 22 ). The clinical activity and safety of Pralsetinib was investigated by the ARROW study(Global multicentric single-arm phase I/II trial) ( 23 ).…”

“…It also demonstrated that it increased kinase activity and conferred resistance through allosteric effects. AXL overexpression and RAS mutations were subsequently reported in two RET fusion-positive cell lines resistant to multikinase inhibitors ( 22 ). Selective RET inhibitors have been designed to overcome gatekeeper mutations.…”

Designing Novel Compounds for the Treatment and Management of RET-Positive Non-Small Cell Lung Cancer—Fragment Based Drug Design Strategy

“…Furthermore, the gatekeeper mutation (V804M and V804L), solvent front (G810A, G810R, H810S and G810C), and other mutations including S904F, Y806C, Y806N, and V738A were observed to be the key factors for disease burden in NSCLC [ 5 ]. Adding together, RET fusion is observed in 1–2% of young non-smoking NSCLC individuals with a high risk of metastasis in the brain.…”