RET-Altered Cancers—A Tumor-Agnostic Review of Biology, Diagnosis and Targeted Therapy Activity

Abstract

RET alterations, such as fusions or mutations, drive the growth of multiple tumor types. These alterations are found in canonical (lung and thyroid) and non-canonical (e.g., gastrointestinal, breast, gynecological, genitourinary, histiocytic) cancers. RET alterations are best identified via comprehensive next-generation sequencing, preferably with DNA and RNA interrogation for fusions. Targeted therapies for RET-dependent cancers have evolved from older multikinase inhibitors to selective inhibitors of RET such as selpercatinib and pralsetinib. Prospective basket trials and retrospective reports have demonstrated the activity of these drugs in a wide variety of RET-altered cancers, notably those with RET fusions. This paved the way for the first tumor-agnostic selective RET inhibitor US FDA approval in 2022. Acquired resistance to RET kinase inhibitors can take the form of acquired resistance mutations (e.g., RET G810X) or bypass alterations.

Agnostic Administration of Targeted Anticancer Drugs: Looking for a Balance between Hype and Caution

“…RET mutations are observed in about a half of medullary thyroid carcinomas and occur at some frequency in neuroendocrine tumors. RET translocations are particularly characteristic for papillary thyroid carcinomas, being detected in approximately 10-20% of these tumors [59][60][61]. RET fusions are also observed in 2-4% of lung adenocarcinomas [62].…”

“…RET rearrangements are also common in colorectal tumors with microsatellite instability and Spitz melanomas. Occasional instances of RET rearrangements have been described in breast carcinomas, KRAS mutation-negative pancreatic cancers, and some other tumor types [37,59,60,[64][65][66]. Two RET inhibitors, selpercatinib and pralsetinib, are the standard treatment option for RET-driven thyroid carcinomas as well as for RET-rearranged non-small cell lung cancers [63,66].…”

Navigating through novelties concerning mCRC treatment—the role of immunotherapy, chemotherapy, and targeted therapy in mCRC

“…RET is a proto-oncogene that produces the receptor for growth factors from the glial-derived neurotrophic factor family ( 144 ). Abnormal chromosomal rearrangements can result in RET fusion, which is most often observed in thyroid and lung cancers, however, in rare instances, RET gene fusion can also occur in mCRC cancer, with a frequency of less than 1% ( 145 ). mCRC tumours with in-frame RET display unique characteristics, such as a preference for the right colon, diagnosis at an older age, and predominantly MSI-h phenotype ( 146 ).…”

RET is a sex-biased regulator of intestinal tumorigenesis

“…Ret, which is critical in enteric nervous system (ENS) development and maintenance, has been implicated as both a proto-oncogene (1) and tumor suppressor (2) in CRC. While RET fusions in metastatic CRC portend a poor prognosis (3), specific RET inhibitors such as selpercatinib and pralsetinib have demonstrated efficacy in targeting oncogenic RET rearrangements [reviewed at (4,5)]. Apc encodes a tumor suppressor and is commonly mutated in CRC.…”