Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment

D Lucas Kerr; Franziska Haderk; Trever G Bivona

doi:10.1016/j.cbpa.2020.11.007

Allosteric SHP2 inhibitors in cancer: Targeting the intersection of RAS, resistance, and the immune microenvironment

Curr Opin Chem Biol. 2021 Jun:62:1-12. doi: 10.1016/j.cbpa.2020.11.007. Epub 2021 Jan 6.

Authors

D Lucas Kerr¹, Franziska Haderk², Trever G Bivona³

Affiliations

¹ Department of Medicine, University of California, San Francisco, CA, USA.
² Department of Medicine, University of California, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA. Electronic address: franziska.haderk@ucsf.edu.
³ Department of Medicine, University of California, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA, USA. Electronic address: trever.bivona@ucsf.edu.

PMID: 33418513
DOI: 10.1016/j.cbpa.2020.11.007

Abstract

The nonreceptor protein tyrosine phosphatase SHP2 (encoded by PTPN11) integrates growth and differentiation signals from receptor tyrosine kinases (RTKs) into the RAS/mitogen-activated protein kinase (MAPK) cascade. Considered 'undruggable' over three decades, SHP2 is now a potentially druggable target with the advent of allosteric SHP2 inhibitors. These agents hold promise for improving patient outcomes, showing efficacy in preclinical cancer models, where SHP2 is critical for either oncogenic signaling or resistance to current targeted agents. SHP2 inhibition may also produce immunomodulatory effects in certain tumor microenvironment cells to help cultivate antitumor immune responses. The first generation of allosteric SHP2 inhibitors is under clinical evaluation to determine safety, appropriate tolerability management, and antitumor efficacy, investigations that will dictate future clinical applications.

Keywords: Allosteric inhibitors; Drug resistance; Immunotherapy; KRAS G12C; SHP2; SHP2 inhibitors; SHP2 review.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review

MeSH terms

Allosteric Regulation / drug effects
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / immunology
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Drug Resistance, Neoplasm
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / immunology
Enzyme Inhibitors / pharmacology
Humans
Immunotherapy
Mitogen-Activated Protein Kinases / metabolism*
Molecular Docking Simulation
Protein Binding
Protein Conformation
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism*
Signal Transduction
Xenograft Model Antitumor Assays
ras Proteins / metabolism*

Substances

Antineoplastic Agents
Enzyme Inhibitors
Receptor Protein-Tyrosine Kinases
Mitogen-Activated Protein Kinases
PTPN11 protein, human
Protein Tyrosine Phosphatase, Non-Receptor Type 11
ras Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding