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.…”

Combination Therapy Approach to Overcome the Resistance to PI3K Pathway Inhibitors in Gynecological Cancers

“…In gynecological cancers, particularly OCs and ECs, the activation of the KRAS pathway and the presence of KRAS mutations are substantial factors contributing to both de novo and acquired resistance against PI3K pathway inhibitors [ 43 ] ( Table 2 ). KRAS pathway activation can act as a compensatory mechanism when the PI3K pathway is inhibited, allowing cancer cells to maintain survival and growth [ 43 , 44 ]. For example, KRAS mutations, which are present in 45% of EC, 30% of OC, and 20% of cervical cancers, often lead to continuous signaling through the KRAS pathway, even in the absence of upstream growth factor stimulation [ 11 ].…”

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).…”