SHP2: A Pleiotropic Target at the Interface of Cancer and Its Microenvironment

Abstract

The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response.

Significance: The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.

Figure 1.

Structure and key mutations on SHP2. A, The overall structure of SHP2 contains three well-folded domains: Two tandem SH2 domains (beige, light green) followed by the PTP (protein tyrosine phosphatase) domain (left); the structure with the N-SH2 domain facing out shows the N-SH2 domain bound on top of the PTP domain, in this view, and shields the active site from access to substrates (middle); right, same view as middle, with the N-SH2 domain removed for clarity, revealing the active site in the PTP domain, in light blue. B, Residues surrounding catalytic C459 residue, and C367, C333, termed “backdoor cysteines,” are in a hydrophobic region of the protein. C, Molecular details of the regions in SHP2 around residues at which GOF (highlighted in green) hotspot mutations in leukemias and Noonan syndrome and LOF (highlighted in red) hotspot mutations occur. Top, left: Hotspot mutations occur around the interaction site between N-SH2 and PTP domains. Residues in the PTP domain (salmon color) that are around the site of the mutation are highlighted in yellow, and residues in the N-SH2 domain (light brown color) that are around the site of the mutation are highlighted in magenta.

Figure 2.

SHP2 is a protein tyrosine phosphatase with pleiotropic function. It is a critical regulator of the RAS–MAPK pathway leading to cancer cell proliferation and growth. In T cells, it is an integral downstream effector of the PD-1 cascade to halt activation and proliferation. In macrophages, it promotes M2 polarization and proliferation and inhibits phagocytosis.

Figure 3.

Combinations of SHP2 with targeted therapy are currently being tested in the clinic. Targets are highlighted in red. For the purpose of clarity, the location of RAS is depicted away from the membrane. Created with BioRender.com.

Figure 4.

Combinations of SHP2 with immune checkpoint inhibitors currently tested in the clinic (top). Schematic model of the changes occurring in the tumor microenvironment upon modulation of SHP2 activity (bottom). Created with BioRender.com.