Signaling pathways and therapeutic interventions in gastric cancer

Abstract

Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

“…To date, surgical resection is considered the main curative treatment option and chemotherapy is the most common treatment for GC [ 2 ]. Standard of first-line therapy for GC typically consists of 5-FU and a platinum-based agent including SOX (S-1 + oxaliplatin), XELOX (oxaliolatin + capecitabine), FOLFOX (leucovorin + 5-FU + oxaliplatin) and FLOT (5-FU + leucovorin + oxaliplatin + docetaxel) [ 3 ]. To date, two targeted therapies have been permitted to use in the clinic: trastuzumab (targeting HER2) and ramucirumab (targeting VEGF) [ 2 , 4 , 5 ].…”

Helicobacter pylori regulated microRNA map of human gastric cells

“…On the contrary, downregulated HP‐hDEmiRs were found to target TGF‐beta signaling, mitosis, translation, and gene silencing. These biological processes are important in cancer progression, and downregulation of the regulatory HP‐hDEmiRs possibly favor the overexpression of these processes 57 . Clearly, this pathogen uses HP‐hDEmiRs as surrogates to alter the host gene expression that paves toward carcinogenesis.…”

Research Progress for Targeting Deubiquitinases in Gastric Cancers

“…Likewise, Zhao et al found that USP28 was highly expressed in GC and was conducive to proliferation and metastasis, mainly due to its ability to increase LSD1 levels [ 53 ]. The same group subsequently designed and synthesized new [ 1 , 2 , 3 ] triazolo [4,5-d] pyrimidine derivatives as potent USP28 inhibitors. Among them, compound 19 potently inhibited USP28 activity with an IC 50 of 1.10 ± 0.02 μM and induced its degradation at higher doses, thereby exhibiting cytotoxic effects against GC cells [ 110 ].…”

“…Based on estimates from the GLOBOCAN database, more than 1 million new GC cases and an estimated 769,000 GC deaths occurred worldwide in 2020 [ 1 ]. As with other cancer types, GC development is a multistage process involving genetic and epigenetic alterations [ 2 , 3 ]. In addition to host factors, other etiological factors, including a high-salt diet, tobacco use, and infectious agents, such as Helicobacter pylori ( H. pylori ) and Epstein–Barr virus (EBV), also play a significant role in the initiation and progression of GC [ 4 ].…”

“…In addition to host factors, other etiological factors, including a high-salt diet, tobacco use, and infectious agents, such as Helicobacter pylori ( H. pylori ) and Epstein–Barr virus (EBV), also play a significant role in the initiation and progression of GC [ 4 ]. Despite advances in understanding the mechanisms underlying GC and improved therapies, almost one-third of patients with GC are diagnosed at a late stage, with a 5-year survival rate below 20% [ 3 , 5 , 6 ]. Therefore, there is an urgent need to develop novel biomarkers and therapeutic targets for treating GC.…”