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Review
. 2023 Nov 13;15(22):5384.
doi: 10.3390/cancers15225384.

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

Alireza Tojjari  1 , Anwaar Saeed  1 , Arezoo Sadeghipour  2 , Razelle Kurzrock  3 , Ludimila Cavalcante  4
Affiliations
Review

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

Alireza Tojjari et al. Cancers (Basel). .

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.

Keywords: PD-L1; SHP2; T-cell; cancer; immunotherapy.

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Conflict of interest statement

A.S. reports research grants (to institution) from AstraZeneca, Bristol Myers Squibb, Merck, Clovis, Exelixis, Actuate Therapeutics, Incyte Corporation, Daiichi Sankyo, Five Prime Therapeutics, Amgen, Innovent Biologics, Dragonfly Therapeutics, KAHR Medical, BioNTech, and advisory board fees from AstraZeneca, Bristol Myers Squibb, Exelixis, Pfizer, and Daiichi Sankyo. R.K. has received research funding from Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance and from the NCI; has received consultant and/or speaker fees and/or acted as an advisory board/consultant for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Inc., Biological Dynamics, Caris, Datar Cancer Genetics, Daiichi, EISAI, EOM Pharmaceuticals, Iylon, LabCorp, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Regeneron, Roche, TD2/Volastra, Turning Point Therapeutics, and X-Biotech; has an equity interest in CureMatch Inc. and IDbyDNA; serves on the Board of CureMatch and CureMetrix; and is a co-founder of CureMatch. L.C. reports consulting or Advisory Role for Actuate Therapeutics, Pliant Therapeutics, Janssen and CDR-Life and has stock and other ownership interests in Actuate Therapeutics. The remaining authors have no relevant financial interests to disclose.

Figures

Figure 1
Figure 1
Structure of SHP2. (A) Two SH2 domains and PTP domain of SHP2. (B) 3D structure of SHP2 in opened (PDB: 6CRF) and closed (PDB: 5EHR) states. (C) Auto-inhibition of SHP2 due to the blocking of the PTP catalytic site by N-SH2. (D) Exposure of the catalytic pocket due to the conformational change of SHP2.
Figure 2
Figure 2
SHP2 is critical in regulating RAS/ERK, PI3K/Akt, and JAK/STAT signaling pathways in cancer cells. These pathways involve cell growth, differentiation, metabolism, and apoptosis. SHP2 positively influences the RAS/ERK signaling pathway. Based on substrate specificity, SHP2 has a dual role in PI3K/Akt and JAK/STAT pathways.
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