Precision therapy for RET-altered cancers with RET inhibitors

Abstract

Rearranged during transfection (RET) is involved in the physiological development of some organ systems. Activating RET alterations via either gene fusions or point mutations are potent oncogenic drivers in non-small cell lung cancer, thyroid cancer, and in multiple diverse cancers. RET-altered cancers were initially treated with multikinase inhibitors (MKIs). The efficacy of MKIs was modest at the expense of notable toxicities from their off-target activity. Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib were successfully translated to the clinic and FDA approved. We summarize the current state-of-the-art therapeutics with preclinical and clinical insights of these novel RET inhibitors, acquired resistance mechanisms, and future outlooks. HighlightsRearranged during transfection (RET) is an oncogenic driver activated by either RET fusions or mutations. RET fusions occur predominantly in 2% of lung cancers and 10-20% of thyroid cancers and in low frequency in an increasing number of diverse cancers.Recently, highly potent and RET-specific inhibitors selpercatinib and pralsetinib have been successfully translated to the clinic and are FDA approved.Data on acquired resistance to RETspecific inhibitors are rapidly emerging but not fully understood. However recent studies have suggested on-target mutations at non-gatekeeper sites or emergence of off-target alterations such as MET amplification or NTRK fusion as mechanisms of acquired resistance.

Novel Inhibitor-Based Therapies for Thyroid Cancer—An Update

“…These potent inhibitors not only improved ORR, but also higher PFS and OS, with a lower rate of AEs was observed [ 162 , 163 ]. Unfortunately, in a number of cases, there were no improvements after treatment and resistance-associated mutations were identified [ 62 , 163 , 164 ]. Several recent studies have shown that both pralsetinib and selpercatinib are inefficient in MTC patients with RET non-gate mutations at the front and at the hinge of the receptor.…”

“…However, strong pralsetinib-resistant L730V/I mutations, located at the roof of the solvent front of the RET ATP-binding site, remained sensitive to selpercatinib in the preclinical study [ 165 ]. These findings highlight the need to develop a next-generation of drugs covering both gatekeeper and non-gatekeeper mutations for on-target resistance, in addition to deciphering patterns of off-target resistance by alternative mechanisms for combinatory therapies [ 62 , 164 ].…”

“…MKI-related toxicities (listed in Table 5 ) are very common and likely reflect target-binding affinities specific to each drug [ 62 , 166 , 167 , 168 , 169 ]. Among the AEs observed during treatment, HT appears to be the most frequent and is managed using standard antihypertensive drugs.…”

“…RET-targeted therapies, based on selpercatinib and pralsetinib, seem to exhibit lower side effects than other FDA-approved treatments ( Table 5 ). The majority of patients tolerate these drugs well, while only a few percent of patients discontinue the therapy due to treatment-related AEs [ 62 , 162 , 163 ]. The most commonly observed AEs of selpercatinib are HT, diarrhoea, fatigue and dry mouth [ 163 ], whereas pralsetinib administration is associated with increased risk of neutropenia and liver impairment as well as decreased white blood cells (WBCs) count [ 162 ].…”

“…The RET alteration determines distinct phenotypes of MTC that may differ in terms of age of disease onset and aggressiveness. For example, malignancies harboring the RET M918T somatic mutation that is the most frequent genetic change in sporadic MTCs, are related to a more aggressive MTC course and worse survival [ 61 , 62 ].…”