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.

FIG 1.

Schematic illustration of RET protein, its ligands, receptors, and signaling pathways. The numbers above the RET domains indicate amino acid positions. The main RET phosphorylation sites are listed together with their binding proteins. CLD, cadherin-like domain; CRD, cysteine-rich domain; GFLs, GDNF-family ligands; GFRα, GDNF-family receptor-α; JM, juxtamembrane; TM, transmembrane domain.

FIG 2.

RET fusion. The chromosomal breakpoints of the RET gene often happen within intron 11 and occasionally in introns 7 and 10. The numbers indicate exons in RET gene. The resulted fusion protein contains the dimerization domain (green) from the fusion partner and the kinase domain (blue) of RET, or both the transmembrane (TM) domain (dark gray) and the kinase domain of RET. Reported fusion partner genes are listed in the figure. Frequencies are derived from COSMIC database. NSCLC, non–small-cell lung cancer; PTC, papillary thyroid cancer.

FIG 3.

RET mutation. Somatic RET mutations in sporadic medullary thyroid cancer (MTC) and among different multiple endocrine neoplasia type 2 (MEN2) phenotypes are shown. The frequencies of somatic mutations are derived from the COSMIC database. The frequencies of mutations in MEN2 are derived from published studies.^- FMTC, familial medullary thyroid carcinoma.

FIG 4.

Oncogenic RET signaling and RET inhibitors.