RET signaling pathway and RET inhibitors in human cancer

TL;DR

This paper reviews the RET signaling pathway's role in cancer and the development of inhibitors to target it, focusing on thyroid and lung cancers.

Contribution

The paper provides a comprehensive review of RET's biological role and the clinical progress of RET inhibitors in cancer treatment.

Findings

RET alterations are most common in thyroid and lung cancers and are linked to poor prognosis and metastasis.

Activating RET mutations drive cancer progression by enhancing downstream signaling pathways like PI3K/AKT and MAPK.

FDA-approved RET inhibitors like Selpercatinib and Pralsetinib show clinical efficacy in treating RET-driven cancers.

Abstract

Rearranged during transfection (RET) receptor tyrosine kinase was first identified over thirty years ago as a novel transforming gene. Since its discovery and subsequent pathway characterization, RET alterations have been identified in numerous cancer types and are most prevalent in thyroid carcinomas and non-small cell lung cancer (NSCLC). In other tumor types such as breast cancer and salivary gland carcinomas, RET alterations can be found at lower frequencies. Aberrant RET activity is associated with poor prognosis of thyroid and lung carcinoma patients, and is strongly correlated with increased risk of distant metastases. RET aberrations encompass a variety of genomic or proteomic alterations, most of which confer constitutive activation of RET. Activating RET alterations, such as point mutations or gene fusions, enhance activity of signaling pathways downstream of RET, namely PI3K/AKT, RAS/RAF, MAPK, and PLCγ pathways, to promote cell proliferation, growth, and survival. Given the important role that mutant RET plays in metastatic cancers, significant efforts have been made in developing inhibitors against RET kinase activity. These efforts have led to FDA approval of Selpercatinib and Pralsetinib for NSCLC, as well as, additional selective RET inhibitors in preclinical and clinical testing. This review covers the current biological understanding of RET signaling, the impact of RET hyperactivity on tumor progression in multiple tumor types, and RET inhibitors with promising preclinical and clinical efficacy.

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