RET V804*

Collectively, BYS10 represents a novel, highly selective RET inhibitor with superior in vitro and in vivo activity against multiple RET alterations compared to Selpercatinib. Its recent Investigational New Drug (IND) approvals from the FDA and NMPA underscore its therapeutic potential for RET-driven malignancies.

The clinical therapeutic benefits of the second-generation RET inhibitor pralsetinib are greatly compromised by acquired resistance mediated by solvent-front mutations (e.g., RETG810R/S/C)...However, the relatively poor pharmacokinetic properties of these compounds will limit their further development. Therefore, compound 7qe might be a promising lead compound for the development of novel RETV804M and RETG810C inhibitors overcoming the clinical acquired resistance.

Optimized pharmacokinetic properties (38.9% oral bioavailability in monkey) and central nervous system penetration support clinical translation. APS03118 is currently in phase Ib trials (NCT05653869) for patients progress on first-generation SRIs, offering a promising strategy to address acquired resistance.

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...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)...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.

The prevalence of MEN2 and PHTS is ∼10-20 times higher than it is currently estimated for the general population. Most affected individuals are not diagnosed with thyroid cancer. Our findings may change the clinical approach to patients with moderate-risk RET mutations.

In 2020, two selective RET inhibitors, selpercatinib and pralsetinib were approved by the US FDA. However, the poor solubility of these compounds will limit their further development. Therefore, compound 8w and 8s might be promising lead compounds for the development of novel RETV804M and RETG810C inhibitors overcoming the clinically acquired resistance.

Although two selective RET inhibitors, selpercatinib and pralsetinib, have been approved by the FDA, acquired resistance through solvent-front mutations has been identified rapidly. Notably, QZ2135 demonstrated in vivo antitumor efficacy in a Ba/F3-KIF5B-RET-G810C xenograft mouse model. Together, this study provides a potential alternative strategy for overcoming acquired resistance to RET inhibitors mediated by solvent-front mutations.

In this cohort study that includes 245,394 genotyped participants in the All of Us Research Program (AoU), the prevalence was 1:2,172 for multiple endocrine neoplasia type 2 (MEN2) and 1:8,764 for PTEN hamartoma syndrome (PHTS). The prevalence of MEN2 and PHPS is ∼10-20 times higher than currently estimated for the general population.

Importantly, in PK/PD studies, 39 exhibited a differentiated and favorable in vivo profile compared to the corresponding tyrosine kinase inhibitor (TKI), compound 3. Robust and sustained degradation of total-RET (tRET) protein and inhibition of phospho-RET (pRET) signaling were observed in TPC-1 xenograft tumors driven by RET and the RET/G810R mutant following a single dose of LDD 39 at 15 and 75 mg/kg, respectively.

OSMR p. G513D may play a role in modifying the evolutionary processes of CLA in subjects co-harboring RET mutations (further studies are necessary to sustain this aspect). Awareness in CLA-positive patients is essential, including the decision of RET testing in selected cases.

P1/2 | "Acquired MoR was identified in 45% of liquid biopsies in the largest prospective dataset studying MoR to RET inhibition. On-target MoR including RET SF G810 muts were more common in MTC than NSCLC. Bypass MoR (30%) included RAS/RAF activating and potentially targetable MET amps."

Our analysis showed results in line with existing studies, except for a considerably lower-than-predicted occurrence of PCC in patients with V804M/L mutations. This study supports the current recommendation regarding the pathogenic variant-dependent management of this rare cancer-associated syndrome.