SHP2 cancer

Protein tyrosine phosphatases (PTPs) are the class of dephosphorylation enzymes that catalyze the removal of phosphate groups from tyrosine residues on proteins responsible for various cellular processes. Any disbalance in signal pathways mediated by PTPs leads to various disease conditions like diabetes, obesity, cancers, and autoimmune disorders. Amongst the PTP superfamily, PTP1B, SHP2, Cdc25, and LMW-PTP have been prioritized as druggable targets for developing medicinal agents. PTP1B is an intracellular PTP enzyme that downregulates insulin and leptin signaling pathways and is involved in insulin resistance and glucose homeostasis...

The antigen processing machinery (APM) components needed for a tumor cell to present an antigen to a T cell are expressed at low levels in solid tumors, constituting an important mechanism of immune escape. More than most other solid tumors, head and neck squamous cell carcinoma (HNSCC) cells tend to have low APM expression, rendering them insensitive to immune checkpoint blockade and most other forms of immunotherapy. In HNSCC, this APM deficiency is largely driven by high levels of EGFR and SHP2, leading to low expression and activation of STAT1; however, recent studies suggest that p53, which is often mutated in HNSCCs, may also play a role...

Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Here, we describe an in situ resistance assay (ISRA) that reliably models acquired resistance to RTK/RAS-pathway-targeted therapies across cell lines. Using osimertinib resistance in EGFR -mutated lung adenocarcinoma (LUAD) as a model system, we show that acquired osimertinib resistance can be significantly delayed by inhibition of proximal RTK signaling using SHP2 inhibitors. Isolated osimertinib-resistant populations required SHP2 inhibition to resensitize cells to osimertinib and reduce MAPK signaling to block the effects of enhanced activation of multiple parallel RTKs...

Kirsten rats sarcoma viral oncogene (KRAS), the first discovered human oncogene, has long been recognized as "undruggable". KRAS mutations frequently occur in multiple human cancers including non-small cell lung cancer(NSCLC), colorectal cancer(CRC) and pancreatic ductal adenocarcinoma(PDAC), functioning as a "molecule switch" determining the activation of various oncogenic signaling pathways. Except for its intrinsic pro-tumorigenic role, KRAS alteration also exhibits an unique immune signature characterized by elevated PD-L1 level and high tumor mutational burden(TMB)...

OBJECTIVE: To investigate the effect of Src homology 2 domain-containing tyrosine phosphatase-2 (SHP2) in tumor-associated macrophages (TAMs), which is mediated by macrophage colony-stimulating factor (M-CSF) secreted by gastric cancer cells, on the development of gastric cancer and its molecular mechanism. METHODS: The progression of gastric cancer was detected by nude mouse tumor-bearing experiments. Colony formation assay and cell counting kit-8 (CCK8) assay were used to detect the proliferation capacity of gastric cancer cells...

The treatment of non-small cell lung cancer (NSCLC) patients harboring a proto-oncogene tyrosine-protein kinase c-ros oncogene 1 (ROS1) fusion gene has greatly benefited from the use of crizotinib. However, drug resistance inevitably occurs after 1 year of treatment. Clinical studies have shown that patients with an L2026M mutation in the ROS1 kinase domain account for about 6% of the total number of crizotinib-resistant cases, which is an important group that cannot be ignored. To explore the mechanism involved, we constructed the HLA class II histocompatibility antigen gamma chain (CD74)-ROS1 L2026M mutant gene by fusion polymerase chain reaction (PCR) and transfected it into H460 and A549 cells...

SHP2 phosphatase plays an important role in regulating several intracellular signaling pathways. Pathogenic mutations of SHP2 cause developmental disorders and are linked to hematological malignancies and cancer. SHP2 comprises two tandemly-arranged SH2 domains, a catalytic PTP domain, and a disordered C-terminal tail. Under physiological, non-stimulating conditions, the catalytic site of PTP is occluded by the N-SH2 domain, so that the basal activity of SHP2 is low. Whereas the autoinhibited structure of SHP2 has been known for two decades, its active, open structure still represents a conundrum...

Src homology 2 domain-containing phosphatase (SHP2) is a non-receptor protein phosphatase that transduces signals from upstream receptor tyrosine kinases (RTKs)/non-RTKs to Ras/MAPK pathway. Accumulating studies indicated that SHP2 is a critical mediator of resistance to current targeted therapies in multiple cancers. Here, we reported a novel SHP2 allosteric inhibitor JC-010a, which was highly selective to SHP2 and bound at the "tunnel" allosteric site of SHP2. The effect of JC-010a on combating RTK/non-RTK or MAPK inhibitors-induced acquired resistance was explored...

Src homology-2 (SH2) domain-containing phosphatase-2 (SHP2) is the first identified protooncogene and is a promising target for developing small molecule inhibitors as cancer chemotherapeutic agents. Pharmacophore-based virtual screening (PBVS) is a pharmacoinformatics methodology that employs physicochemical knowhow of the chemical space into the dynamic environs of computational technology to extract virtual molecular hits that are precise and promising for a drug target. In the current study, PBVS has been applied on EnamineTM Advanced Collection of 551,907 molecules by using a pharmacophore model developed upon SHP099 by Molecular Operating Environment (MOE) software to identify potential small molecule allosteric SHP2 inhibitors...

SHP2 phosphatase promotes full activation of the RTK-dependent Ras/MAPK pathway. Its mutations can drive cancer and RASopathies, a group of neurodevelopmental disorders (NDDs). Here we ask how same residue mutations in SHP2 can lead to both cancer and NDD phenotypes, and whether we can predict what the outcome will be. We collected and analyzed mutation data from the literature and cancer databases and performed molecular dynamics simulations of SHP2 mutants. We show that both cancer and Noonan syndrome (NS, a RASopathy) mutations favor catalysis-prone conformations...

OBJECTIVE: Currently, multiple studies have shown that long non-coding ribonucleic acid TUSC7 exerts an anti-tumor effect in a variety of cancers. However, the function and underlying regulatory mechanism of lncRNA TUSC7 in CRC remain unclear. METHODS: The relative fluorescence intensity of MMP9 in the cancer and in peritoneal tissues was measured by immunofluorescence. Peritoneal macrophages in BALB/c mice were sorted out using flow cytometry. The abdominal circumference of mice was measured...

Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancers with mutations predominantly occurring in codon 12. These mutations disrupt the normal function of KRAS by interfering with GTP hydrolysis and nucleotide exchange activity, making it prone to the GTP-bound active state, thus leading to sustained activation of downstream pathways. Despite decades of research, there has been no progress in the KRAS drug discovery until the groundbreaking discovery of covalently targeting the KRASG12C mutation in 2013, which led to revolutionary changes in KRAS-targeted therapy...

SHP2 (Src Homology 2 Domain-Containing Phosphatase 2) is a protein tyrosine phosphatase widely expressed in various cell types. SHP2 plays a crucial role in different cellular processes, such as cell proliferation, differentiation, and survival. Aberrant activation of SHP2 has been implicated in multiple human cancers and is considered a promising therapeutic target for treating these malignancies. The PTPN11 gene and functions encode SHP2 as a critical signal transduction regulator that interacts with key signaling molecules in both the RAS/ERK and PD-1/PD-L1 pathways; SHP2 is also implicated in T-cell signaling...

Mutations in the receptor tyrosine kinases (RTKs) FLT3 and KIT are frequent and associated with poor outcomes in acute myeloid leukemia (AML). Although selective FLT3 inhibitors (FLT3i) are clinically effective, remissions are short-lived due to secondary resistance characterized by acquired mutations constitutively activating the RAS/MAPK pathway. Hereby, we report the pre-clinical efficacy of co-targeting SHP2, a critical node in MAPK signaling, and BCL2 in RTK-driven AML. The allosteric SHP2 inhibitor RMC-4550 suppresses proliferation of AML cell lines with FLT3 and KIT mutations, including cell lines with acquired resistance to FLT3i...

Tanshinone is a lipophilic compound that is present in traditional Chinese medicine and is derived from the roots of Salvia miltiorrhiza (Danshen). It has been proven to be highly effective in combating tumors in various parts of the body, including liver carcinoma, gastric cancer, ovarian cancer, cervix carcinoma, breast cancer, colon cancer, and prostate cancer. Tanshinone can efficiently prevent the reproduction of cancerous cells, induce cell death, and inhibit the spread of cancerous cells, which are mainly involved in the PI3K/Akt signaling pathway, NF-κB pathway, Bcl-2 family, Caspase cascades, MicroRNA, MAPK signaling pathway, p21, STAT3 pathway, miR30b-P53-PTPN11/SHP2 axis, β-catenin, and Skp2...

Targeting SHP2 has become a potential cancer treatment strategy. In this study, ellagic acid was first reported as a competitive inhibitor of SHP2, with an IC50 value of 0.69 ± 0.07 μM, and its inhibitory potency was 34.86 times higher that of the positive control NSC87877. Ellagic acid also had high inhibitory activity on the SHP2-E76K and SHP2-E76A mutants, with the IC50 values of 1.55 ± 0.17 μM and 0.39 ± 0.05 μM, respectively...

UNLABELLED: Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated non-small cell lung cancer (NSCLC) and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the cyclin-dependent kinase 4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition...

Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γc ). PD-1 ligation also activates SHP2, which dephosphorylates γc Y357 , leading to impairment of γc family cytokine-triggered signaling...

To boost KRASG12C inhibitor efficacy and counter cancer cells' ability to mount resistance, combination strategies are being utilized. Findings from the phase III CodeBreaK 300 trial indicate that adding the EGFR inhibitor panitumumab to sotorasib bests standard care for chemorefractory KRASG12C colorectal cancer. Joint SHP2 blockade is another approach that shows signs of activity in reversing acquired KRASG12C inhibitor resistance, according to preliminary phase I data.

Triple negative breast cancer (TNBC) presents a formidable challenge due to the lack of effective treatment modalities. Immunotherapy stands as a promising therapeutic approach; however, the emergence of drug resistance mechanisms within tumor cells, particularly those targeting apoptosis and pyroptosis, has hampered its clinical efficacy. SHP2 is intricately involved in diverse physiological processes, including immune cell proliferation, infiltration, and tumor progression. Nevertheless, the precise contribution of SHP2 to tumor cell pyroptosis resistance remains inadequately understood...