Activating Mutation of SHP2 Establishes a Tumorigenic Phonotype Through Cell-Autonomous and Non-Cell-Autonomous Mechanisms

Abstract

Gain-of-function mutation of SHP2 is a central regulator in tumorigenesis and cancer progression through cell-autonomous mechanisms. Activating mutation of SHP2 in microenvironment was identified to promote cancerous transformation of hematopoietic stem cell in non-autonomous mechanisms. It is interesting to see whether therapies directed against SHP2 in tumor or microenvironmental cells augment antitumor efficacy. In this review, we summarized different types of gain-of-function SHP2 mutations from a human disease. In general, gain-of-function mutations destroy the auto-inhibition state from wild-type SHP2, leading to consistency activation of SHP2. We illustrated how somatic or germline mutation of SHP2 plays an oncogenic role in tumorigenesis, stemness maintenance, invasion, etc. Moreover, the small-molecule SHP2 inhibitors are considered as a potential strategy for enhancing the efficacy of antitumor immunotherapy and chemotherapy. We also discussed the interconnection between phase separation and activating mutation of SHP2 in drug resistance of antitumor therapy.

Keywords: SHP2 inhibition; SHP2 mutation; cell-autonomous/non-cell autonomous mechanisms; tumor; tumor microenvironment.

FIGURE 1

The structure and function regulation of SHP2. SHP2 contains 593 amino acids, including various important active regulatory sites. When these sites are mutated, SHP2 gains or loses function. The D-E ring and P ring on the three-dimensional structure of SHP2 play an important role in regulating catalytic activity. When SHP2 is in self-inhibition state, the P ring on the PTP domain will cover the D-E ring on the N-SH2 domain. SHP2 is activated by gain-of-function mutations, such as E76K, or inactivated by loss-of-function mutations, such as Q510E.

FIGURE 2

The oncogenic function of tumor cell-autonomous SHP2 gain-of-function mutations. As a signaling hub, SHP2 affects various tumor developmental stages by regulating multiple signaling pathways, such as PI3K/Akt, Ras/Raf/MEK/Erk signaling. SHP2 promotes proliferation, differentiation, and invasion and maintains stemness of cancer stem cells via activation of β-catenin and Ras/Erk signaling.

FIGURE 3

SHP2 mutation in bone marrow microenvironment promotes myeloproliferative neoplasm. PTPN11 mutation induced by Prx1-cre, Nestin-cre, Osterix-cre, and Lepr-cre in mesenchymal stem cells promotes tumorigenicity of hematopoietic stem cells, whereas PTPN11 mutation induced by VE-Cadherin-cre in endothelial cells and Oc-cre in osteoblasts shows no myeloproliferative neoplasm formation-promoting effect.

FIGURE 4

The oncogenic role of SHP2 in tumor immune microenvironment. SHP2 binds to the T cell receptor (TCR) and prevents the activation of T cell induced by the signaling transduction among tumor cells, antigen-presenting cells (APCs), and T cells. SHP2 binds to the colony-stimulating factor-1 receptor (CSF-1R) under the stimulation of CSF-1 and then consequently activates Ras/Raf/MEK/Erk signaling and promotes the proliferation of tumor-associated macrophage (TAM), thus boosting the cancer cell survival. SHP2 in T cells inhibits the activation of T cell via blockage of the function of CD28 and STAT1.

FIGURE 5

Combination of SHP099 with other drugs enhances antitumor efficacy. In patient-derived xenograft (PDX) mouse model, temozolomide (TMZ) combines with SHP099 to increase the survival rate of tumor-carrying mice. The combination of SHP099 with MEK inhibitor, Erk inhibitor, ALK inhibitor, or sorafenib impairs the survival of malignancies, which indicates that the drug toxicity is enhanced through the drug combination.