Overcoming Immune Checkpoint Therapy Resistance with SHP2 Inhibition in Cancer and Immune Cells: A Review of the Literature and Novel Combinatorial Approaches

Author:

Tojjari Alireza1ORCID,Saeed Anwaar1,Sadeghipour Arezoo2ORCID,Kurzrock Razelle3,Cavalcante Ludimila4ORCID

Affiliation:

1. UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232, USA

2. Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modarres University, Tehran P.O. Box 14115-175, Iran

3. Department of Medicine, Genome Sciences and Precision Medicine Center, Medical College of Wisconsin Cancer Center, Milwaukee, WI 53226, USA

4. Novant Health Cancer Institute, Charlotte, NC 28204, USA

Abstract

SHP2 (Src Homology 2 Domain-Containing Phosphatase 2) is a protein tyrosine phosphatase widely expressed in various cell types. SHP2 plays a crucial role in different cellular processes, such as cell proliferation, differentiation, and survival. Aberrant activation of SHP2 has been implicated in multiple human cancers and is considered a promising therapeutic target for treating these malignancies. The PTPN11 gene and functions encode SHP2 as a critical signal transduction regulator that interacts with key signaling molecules in both the RAS/ERK and PD-1/PD-L1 pathways; SHP2 is also implicated in T-cell signaling. SHP2 may be inhibited by molecules that cause allosteric (bind to sites other than the active site and attenuate activation) or orthosteric (bind to the active site and stop activation) inhibition or via potent SHP2 degraders. These inhibitors have anti-proliferative effects in cancer cells and suppress tumor growth in preclinical models. In addition, several SHP2 inhibitors are currently in clinical trials for cancer treatment. This review aims to provide an overview of the current research on SHP2 inhibitors, including their mechanism of action, structure-activity relationships, and clinical development, focusing on immune modulation effects and novel therapeutic strategies in the immune-oncology field.

Publisher

MDPI AG

Subject

Cancer Research,Oncology

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. HDAC-targeting epigenetic modulators for cancer immunotherapy;European Journal of Medicinal Chemistry;2024-02

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