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.

Enzyme Is the Name – Adapter Is the Game

“…The tyrosine phosphatase SHP2, the product of the PTPN11 proto-oncogene, represents a key signaling protein and proto-oncogene product in the RAS/ERK pathway. SHP2 consists of two Nterminally located SH2 domains arranged in tandem (N-SH2 and C-SH2), followed by the catalytic domain and a C-terminal tail containing a regulatory bipartite tyrosine phosphorylation motif, implicated in sustaining SHP2 activation [63,64]. In its inactive state, SHP2 resides in a closed autoinhibited conformation stabilised by the binding of the tandem SH2 domain to the catalytic domain.…”

“…In its inactive state, SHP2 resides in a closed autoinhibited conformation stabilised by the binding of the tandem SH2 domain to the catalytic domain. In the presence of tyrosine-phosphorylated proteins, e.g., tails of RTKs, the tandem SH2 domain will be displaced from the catalytic domain, thereby allowing its access to substrates [63] . The majority of these substrates remain ill-defined [65] and its positive influence on RAS/ERK pathway activation appears to be manifold, incl.…”

Spatial interaction and functional status of CD68+SHP2+ macrophages in tumor microenvironment correlate with overall survival of NSCLC

“…Here, we summarize the SHP2related drugs currently in clinical trials in Supplementary Table S1. The noteworthy aspect is that SHP2 also plays an important role in the regulation of immune responses (17)(18)(19). The involvement of SHP2 in the downstream signaling of PD-1, a pivotal immune checkpoint target for cancer immunotherapy, has been observed in T cells (20).…”

Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors

“…3 Because of its role in regulating signaling cascades, therapeutic approaches where SHP2 inhibition is combined with an inhibitor of RAS or certain receptor tyrosine kinases (RTKs) are of increasing interest. 4 Early efforts to take advantage of the therapeutic potential of SHP2 inhibition led to the identification of active-site binders that showed reasonable potency and modest selectivity over closely related phosphatases but had a limited path forward as orally available drugs because of their unfavorable physicochemical properties. 5 It was not until several years later that Chen et al 6,7 transformed the SHP2 field with their report that the enzyme could be locked into an inactive conformation with drug-like allosteric inhibitors.…”