State-of-the-Art Strategies for Targeting RET-Dependent Cancers

Abstract

Activating receptor tyrosine kinase RET (rarranged during transfection) gene alterations have been identified as oncogenic in multiple malignancies. RET gene rearrangements retaining the kinase domain are oncogenic drivers in papillary thyroid cancer, non–small-cell lung cancer, and multiple other cancers. Activating RET mutations are associated with different phenotypes of multiple endocrine neoplasia type 2 as well as sporadic medullary thyroid cancer. RET is thus an attractive therapeutic target in patients with oncogenic RET alterations. Multikinase inhibitors with RET inhibitor activity, such as cabozantinib and vandetanib, have been explored in the clinic for tumors with activating RET gene alterations with modest clinical efficacy. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects, such as hypertension, rash, and diarrhea. This resulted in a narrow therapeutic index of these drugs, limiting ability to dose for clinically effective RET inhibition. In contrast, the recent discovery and clinical validation of highly potent selective RET inhibitors (pralsetinib, selpercatinib) demonstrating improved efficacy and a more favorable toxicity profile are poised to alter the landscape of RET-dependent cancers. These drugs appear to have broad activity across tumors with activating RET alterations. The mechanisms of resistance to these next-generation highly selective RET inhibitors is an area of active research. This review summarizes the current understanding of RET alterations and the state-of-the-art treatment strategies in RET-dependent cancers.

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…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].…”

“…1 Some RET fusions (EPHA5-RET, KHDRBS1-RET, PICALM-RET, SQSTM1-RET) are listed here but not reported in Figure 1 because of the lack of information about the involved exon. Moreover, additional RET fusion partners have been recently listed but without molecular details: CLIP1 and PRKG1 (15) and EML4 and PARD3 (14). 2 The involved RASGEF1A (Rat Sarcoma Guanine nucleotide Exchange Factor) portion (5'-UTR) is non-coding; thus, this fusion generates a truncated RET (∆RET) protein starting at a cryptic ATG site in RET exon 11.…”

“…RET fusions occur in~10%-20% of sporadic PTCs [15,18]. In the TCGA study, enrolling almost 500 PTC samples,~6.8% of cases harbored a RET fusion [24].…”

“…In LADC, RET fusions are reported to be associated with young age (<60 years), female gender, Asian ethnicity, and minimal tobacco exposure [17]. RET fusions were also associated with poor differentiation, solid subtype, presence of signet ring cells, small tumor size, early lymph node metastases, low levels of PD-L1 expression, and poor response to immunotherapy [13,15,17]. In vitro irradiation with -rays generated KIF5B-RET fusion in lung cells, thus pointing, similar to thyroid cancer, to radiation as a possible risk factor for RET fusion in lung cancer [117].…”

“…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].…”