Abstract
The protein tyrosine phosphatase SHP2, encoded by PTPN11, functions as a critical signal transduction regulator and interacts with key signaling molecules in both RAS/ERK and PD-1/PD-L1/ BTLA (B- and T-lymphocyte attenuator) pathways. Targeting SHP2 pharmacologically, therefore, may be a promising therapeutic strategy for many RAS-driven cancers.
Highlights
The SHP2 phosphatase consists of one protein tyrosine phosphatase catalytic domain (PTP domain), two tandem Src homology 2 (SH2) domains (N-SH2 and C-SH2), and a C-terminal tail with two tyrosine phosphorylation sites (Tyr542 and Tyr580) [1] (Figure 1A)
SHP2 activity is normally auto-inhibited by the binding of the N-SH2 domain with the PTP domain [2]
Upon stimulation of growth factors or cytokines, the N-SH2 domain binds to specific phospho-tyrosine residues and induces a conformational change that leads to exposure of the PTP domain and an increase in the catalytic activity [3] (Figure 1B)
Summary
RAS/ERK signaling activation is associated with significantly reduced levels of tumor-infiltrating lymphocytes (TIL), thereby potentially facilitating immune evasion by the tumor cells [62]. A previous study reported a marked depletion of TAM and a shift from M2 to M1 TAM upon CSF1R inhibition, and demonstrated the combination benefit of co-targeting CSF1R and mTOR using PLX3397 and rapamycin in an MPNST xenograft model [87], which provided a translational basis for the MPNSTspecific prospective phase 2 clinical trial (NCT02584647). Preliminary data from this trial reported objective responses and durable stable disease in MPNST patients treated with PLX3397 and sirolimus [88]. SHP2 inhibitor Combination partner (target) Phase single agent; nazartinib [EGFR]
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