SHP2 in Cancer: From Tumor Biology to Therapeutic Targeting

SHP2 is a tyrosine phosphatase that mediates intracellular signaling downstream of transmembrane receptors regulated by a pair of src homology 2 (SH2) domains. Its overexpression and mutation are pivotal in driving tumor progression by influencing various cancer's fundamental characteristics, such as metastasis, DNA repair, angiogenesis, immunosuppression, and telomere extension. SHP2 acts as a convergent node of oncogenic signaling pathways including MAPK, PI3K-AKT, VEGF, JAK-STAT making it an attractive target for cancer therapeutics. Preclinical studies demonstrate that SHP2 allosteric inhibitors in combination with EGFR, PD-1, KRAS, or MEK inhibitors, show potent antitumour activity and effectively overcome adaptive resistance beyond conventional therapies. Multiple SHP2 allosteric inhibitors are currently in clinical trials to assess their effectiveness, safety, and tolerability in treating various malignancies. Despite these advancements, SHP2's complex role presents challenges for the efficacy of SHP2 monotherapy and in the context of SHP2 mutants. Current allosteric inhibitors lack a well-defined mode of action for selectively targeting hyperactive SHP2 in malignancies. Moreover, a deeper understanding of SHP2's regulatory mechanisms and its interactions within the tumor microenvironment is needed to optimize SHP2-directed therapies. This review highlights these challenges, with a focus on SHP2 regulation, disease-associated mutants, its role in cancer cells and the tumor microenvironment, current and future therapeutic prospects.