Can New Structure of RET Inhibitors Capable of Suppressing Resistant in Non-Small-Cell Lung Cancer?

Review Article

Austin J Pharmacol Ther. 2023; 11(3):1178.

Can New Structure of RET Inhibitors Capable of Suppressing Resistant in Non-Small-Cell Lung Cancer?

Jiayi Shen¹; Liping Chen¹; Yulan Song¹; Sheng Chen²*; Wei Guo¹*; Yongdong Li¹*

¹Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi 341000, PR China

²Jiangxi Chiralsyn Biological Medicine Co., LTD, China

*Corresponding author: Wei Guo & Yongdong Li Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi 341000, PR China;

Sheng Chen, Jiangxi Chiralsyn Biological Medicine Co., LTD, China. Tel: +86 797 8393670; Fax: +86 797 8393670 Email: guoweigw@126.com; ydli2011@163.com; chensheng0813@163.com

Received: October 11, 2023 Accepted: November 18, 2023 Published: November 25, 2023

Abstract

In 2012, RET rearrangements are observed in 1-2% of Non-Small-Cell Lung Cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. Several compounds have been reported, including some traditional kinases inhibitors and the discovery of some new structure of natural products. Cabozantinib and vandetanib are multikinase inhibitors have been explored in the clinic for NSCLC patients. As a result of the nonselective nature of these multikinase inhibitors, patients had off-target adverse effects. Then, the discovery and clinical validation of highly potent selective RET inhibitors such as pralsetinib and selpercatinib demonstrating improved effificacy and a more favorable toxicity profile. However, acquired resistance mediated by secondary mutations in the solvent-front region of the kinase (e.g. G810C/S/R) becomes a major challenge for selective RET inhibitor therapies. In this review, we will highlight typical RET inhibitors developed during these years and provide a reference for more potential RET inhibitors exploration in the future.

Keywords: REarranged during transfection (RET) kinase; Non-small cell lung cancer (NSCLC); Resistance; Inhibitors

Introduction

Lung cancer is the most common oncological disease, which is responsible for 11.6 % and 18.4 % of global cancer morbidity and mortality, respectively. It is classified for Small-Cell Lung Cancer (SCLC) and Non-Small Cell Lung Cancer (NSCLC). NSCLC is significantly more common than SCLC that accounts for about 85% and is further subdivided for squamous and non-squamous histological types [1]. Like other common NSCLC drivers, such as sensitizing Epidermal Growth Factor Receptor (EGFR) mutations and Anaplastic Lymphoma Kinase (ALK) or c-Rosproto-Oncogene 1 (ROS1) rearrangements, the oncogenic Rearranged during Transfection (RET) gene fusion was first identified in 2012 that was tend to occur in approximately 1-2 % of NSCLC and it was found to be more common in non-smoking or light smoking, young lung adenocarcinoma patients. RET gene was derived by DNA rearrangement during transfection of mouse NIH3T3 cells with human lymphoma DNA and located in the long arm of human chromosome 10 [2]. It encodes a receptor tyrosine kinase protein composed of 1143 transmembrane amino acid residues, and and consists of three regions. Up to now, 48 unique fusion partners in RET have been identified, such as KIF5B-RET, CCDC6-RET, and NCOA4-RET et al., [3]. These fusions lead to ligand-independent constitutive activation of the RET pathway and increased oncogenic signaling, resulting in RET gene overexpression. Interestingly, RET fusions were mutually exclusive with other oncogenic driver genes [4]. As patients harboring RET aberrations, selectively inhibiting the kinase is a promising therapeutic strategy [5].

For the treatment of NSCLC patients with RET alterations, several Multiple-targeted Kinase Inhibitors (MKIs) were approved [6,7]. Horeover, limited clinical benefits, relatively low tolerated doses, obvious adverse effects and mutations in the kinase prevent the broad application of these multiple-targeted drugs [8-14]. In 2020, two selective RET inhibitors, selpercatinib and pralsetinib were approved by US Food and Drug Administration (FDA). Several other highly promising selective RET inhibitors were also developed in different stages of clinical investigation [15-35]. However, acquired resistance conferred by secondary mutations were also identified. In this review, we focus on the present state of the RET inhibitors in the treatment of NSCLC, discuss the future perspectives for RET positive NSCLC patients and provide an updated panorama of this topic.

The Structure of RET

In 1985, Takahashi et al. [2] identified the protooncogene RET is a transforming gene located in the long arm of human chromosome 10 and was derived by DNA rearrangement during transfection of mouse NIH3T3 cells with human lymphoma DNA. The RET gene encodes a Receptor Tyrosine Kinase (RTK) protein composed of 1143 transmembrane amino acid residues and contains a large extracellular domain, a transmembrane domain and an intracellular tyrosine kinase domain [36]. The RET protein formed by in-frame fusion of the 5'-terminus of a chaperone gene with the 3'-terminus of RET containing its kinase structural domain [37]. The extracellular domain contains four Cadherin-Like Domains (CLD1-4), calcium binding site that between CLD2 and CLD3, a cysteine-richdomain and a conserved cysteinerich domain (Figure 1). Then, as the intracellular region contains a tyrosine kinase domain and tyrosine phosphorylation sites located next to the C terminal region. The C-terminal tail of RET has two major forms, which diverge after residue G1063 because of alternative splicing a short 9-amino acid one (RET9) and a long 51-amino acid one (RET51). Although the two isoforms share a largely common sequence and are coexpressed in many tissues, numerous studies have demonstrated differences in their temporal and spatial regulation of expression, cellular localization and trafficking and biologic functions. It has been suggested that RET51 is the more prominent isoform in tumors and it is more effective than RET9 at promoting cell proliferation, migration and anchorage-independent growth [38,39]. The combination of the intracellular kinase structural domain of RET and the coiled helix structural domain of the chaperone gene, leading to ligand-independent homodimerization and activation of RET by autophosphorylation tyrosine kinase, which in turn activates downstream pathways leading to tumorigenesis and development [36]. RET as the receptor is activated by the ligands and the function of the RET receptor which will be discussed as followed.