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

SIMPLE SUMMARY: REarranged during Transfection (RET) is an emerging target for several types of cancer, including non-small cell lung cancer (NSCLC). The recent U.S. FDA approval of pralsetinib and selpercatinib raises issues regarding the emergence of secondary mutations and amplifications involved in parallel signaling pathways and receptors, liable for resistance mechanisms. The aim of this review is to explore recent knowledge on RET resistance in NSCLC in pre-clinic and in clinical settings and accordingly, the state-of-the-art in new drugs or combination of drugs development. 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.