Overcoming resistance in RET-altered cancers through rational inhibitor design and combination therapies

RET tyrosine kinase, a key regulator of cellular signaling, is abnormally activated due to mutations or fusions in various cancers, making it an important therapeutic target. Traditional multi-kinase inhibitors (MKIs, such as cabozantinib and vandetanib) exhibit significant side effects due to non-selective inhibition of targets like VEGFR, and also suffer from resistance associated with RET mutations (e.g., V804L/M, G810C/S/R), both of which limit their clinical application. Second-generation RET inhibitors (such as selpercatinib and pralsetinib) significantly improve efficacy and safety by precisely targeting the RET ATP binding domain, and have the ability to penetrate the blood-brain barrier, showing remarkable effects on patients with brain metastases. However, they still face challenges of drug resistance due to solvent front mutations (G810C/S/R) and activation of bypass signals. To overcome drug resistance, the design strategies of novel inhibitors focus on multi-target inhibition (such as PLM-101 targeting RET/YES1/FLT3, TPX-0046 targeting RET/SRC), structural optimization (such as helical ring derivatives enhancing binding stability), and natural compound screening (such as ZINC series molecules). The combination therapy strategy effectively reverses drug resistance and enhances efficacy by inhibiting bypass pathways (such as MET, FGFR, Hedgehog-Gli) or epigenetic regulation (such as CDK8/STAT1). For instance, selpercatinib combined with crizotinib can inhibit MET amplification-driven resistance, while arsenic trioxide combined with pralsetinib restores sensitivity by inhibiting the HH-Gli pathway. Current clinical trials show that novel RET inhibitors such as SY-5007 have a significant objective response rate in advanced RET fusion-positive non-small cell lung cancer and are safer than traditional drugs. In the future, it is necessary to further develop broad-spectrum mutation coverage and highly selective inhibitors, and explore individualized combination treatment regimens to improve prognosis. This article systematically reviews the progress, resistance mechanisms and coping strategies of RET-targeted therapy, providing a theoretical basis and direction for the development of precision anti-cancer drugs.