Novel targeted therapeutics for MEN2

Abstract

The rearranged during transfection (RET) proto-oncogene was recognized as the multiple endocrine neoplasia type 2 (MEN2) causing gene in 1993. Since then, much effort has been put into a clear understanding of its oncogenic signaling, its biochemical function and ways to block its aberrant activation in MEN2 and related cancers. Several small molecules have been designed, developed or redirected as RET inhibitors for the treatment of MEN2 and sporadic MTC. However, current drugs are mostly active against several other kinases, as they were not originally developed for RET. This limits efficacy and poses safety issues. Therefore, there is still much to do to improve targeted MEN2 treatments. New, more potent and selective molecules, or combinatorial strategies may lead to more effective therapies in the near future. Here, we review the rationale for RET targeting in MEN2, the use of currently available drugs and novel preclinical and clinical RET inhibitor candidates.

The evolving clinical, genetic and therapeutic landscape of multiple endocrine neoplasia type 2

“…Similar RET rearrangements have been found, albeit less frequently, in colon tumors and chronic myelomonocytic leukemia, while increased RET expression in general is associated with malignant phenotypes in a variety of cancers, including carcinomas of the pancreas and breast (Mulligan 2014, Romei et al 2016. These findings have greatly expanded the patient populations that may benefit from RET-targeted therapies, and preclinical and early clinical trials of RET inhibition in these contexts are already underway (Redaelli et al 2018).…”

“…In addition to surgical management, MEN2 has provided an ideal opportunity for precision medicine interventions using tyrosine kinase inhibitors to block RET activity. The current clinical use of previously developed and re-directed smallmolecule multi-kinase inhibitors, such as vandetanib and cabozantinib, in patients with advanced or metastatic MTC, has prolonged progression-free survival and stable disease, most notably for patients with the more aggressive MEN2B phenotype (Redaelli et al 2018, Wells 2018). Yet, the poor efficacy and safety risks associated with off-target effects of these therapeutics leave much to be improved.…”

“…Yet, the poor efficacy and safety risks associated with off-target effects of these therapeutics leave much to be improved. In 'Novel targeted therapeutics for MEN2', Sara Redaelli and coworkers discuss the burgeoning growth in development or repositioning of novel RET-specific smallmolecule therapeutics currently in preclinical testing or early clinical trials (Redaelli et al 2018). They also provide us with a glimpse of new drugs on the horizon from recent patent filings and discuss the development of combinatorial therapeutic strategies using standard chemotherapy with tyrosine kinase inhibitors or the addition of these inhibitors as second-or even third-line therapies in RET-associated cancers.…”

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…Instead, RET fusions, occurring at the somatic level, are typical of papillary thyroid carcinoma, lung adenocarcinoma, and few other cancers. This notion has made RET an attractive molecular target for small molecule tyrosine kinase inhibitors (TKI) [11][12][13][14]. In this frame, novel selective RET TKIs have featured promising results in clinical investigation [14,15].…”

“…Clinically, there is strong interest in RET TKIs for the targeted treatment of NSCLC [11][12][13][14][15]114]. Interestingly, RET fusions (CCDC6-RET, NCOA4-RET, and the newly described CDC123-RET) have been reported as an acquired resistance mechanism of LADC to EGFR or ALK tyrosine kinase inhibitors [118][119][120].…”