Search Results (128)

Background/Objectives: The dual targeting of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) represents an effective approach for cancer treatment. The current study involved the design, synthesis, and biological evaluation of a new series of purine-containing hydrazones, 6–24 (a,b), as anticancer agents targeting EGFR and HER2 kinases. Methods: The proposed compounds were initially screened in silico using molecular docking to investigate their binding affinity to the active sites of EGFR and HER2 kinase domains. Subsequently, the compounds were synthesized and evaluated in vitro for their antiproliferative activity, using the MTT assay, against the various cancer cell lines A549, SKOV-3, A2780, and SKBR-3, with lapatinib as the reference drug. The most active derivatives were then examined to determine their inhibitory activity against EGFR and HER2 kinases. Results: Among the assessed compounds, significant antiproliferative activity was demonstrated by 19a, 16b, and 22b. 19a exhibited substantial anticancer efficacy against A549 and SKBR-3, with IC₅₀ values of 0.81 µM and 1.41 µM, respectively. This activity surpassed lapatinib, which has an IC₅₀ of 11.57 µM on A549 and 8.54 µM on SKBR-3 cells. Furthermore, 19a, 16b, and 22b exhibited superior EGFR inhibitory efficacy compared with lapatinib (IC₅₀ = 0.13 µM), with IC₅₀ values of 0.08, 0.06, and 0.07 µM, respectively. Regarding HER2, 22b demonstrated the greatest potency with an IC₅₀ of 0.03 µM, equipotent to lapatinib (IC₅₀ = 0.03 µM). Flow cytometry analysis of A549 cells treated with 19a and 22b indicated their ability to arrest the cell cycle during the G1 phase and to trigger cellular apoptosis. Conclusions: Compounds 19a, 16b, and 22b represent intriguing candidates for the development of an anticancer agent targeting EGFR and HER2 kinases. Full article

We previously reported that the level of EGFR expression is directly associated with the survival rate of estrogen receptor-positive (ER+) breast cancer patients. Here, we investigated how ER activation by 17β-estradiol (E2), the most potent form of estrogen, affects the expression or activity of EGFR or EGFR-related genes in ER+ breast cancer cells. As expected, E2 enhanced cell proliferation, the induction of S phase, and tumor growth in ER+ breast cancer models. E2 also increased the expression of secretory proteins, including amphiregulin (AREG), angiogenin, artemin, and CXCL16. We focused on AREG, which is a ligand of the epidermal growth factor receptor (EGFR). The levels of AREG expression were positively correlated with ESR1 expression. Our results also showed higher AREG mRNA expression levels in ER+ breast cancer cells than in ER- breast cancer cells. We treated ER+ breast cancer cells with lapatinib to inhibit the AREG/EGFR signaling pathway and then completely inhibited E2-induced cell proliferation and S-phase induction. Similar to the lapatinib treatment, cell proliferation, S-phase induction, cell migration, and tumor growth were suppressed by AREG knockdown. Taken together, we demonstrated that the induction of AREG by E2 contributes to EGFR activation, which then affects cell proliferation and tumor growth. Therefore, we suggest that AREG acts as an intermediary between EGFR and ER and targeting both ERs and EGFRs through combination therapy could prevent tumor progression in EGFR+ ER+ breast cancer patients. Full article

Resistance to HER2 tyrosine-kinase inhibitor Lapatinib (Lap) is one of the leading causes of cancer treatment failure in HER2+ breast cancer (BC), associated with an aggressive tumor phenotype. Cryptotanshinone (Cry) is a natural terpene molecule that could function as a chemosensitizer by disturbing estrogen receptor (ERα) signaling and inhibiting the protein translation factor-4A, eIF4A. Therefore, we evaluated Cry dual regulation on eIF4A and ERα. This study aimed to elucidate the underlying mechanisms of Lap chemoresistance and the impact of Cry on them. We generated two Lap-resistant BT474 cell HER2+ variants named BT474^LapRV1 and BT474^LapRV2 with high chemoresistance levels, with 7- and 11-fold increases in EC₅₀, respectively, compared to BT474 parental cells. We found a PDCD4-p70S6Kβ axis association with Lap chemoresistance. However, a concomitant down-regulation of the RAF-MEK-ERK cell survival pathway and NF-κB was found in the chemoresistant cell variants; this phenomenon was exacerbated by joint treatment of Cry and Lap under a Lap plasmatic reported concentration. Optimized calcium management was identified as a compensatory mechanism contributing to chemoresistance, as determined by the higher expression of calcium pumps PMCA1/4 and SERCA2. Contrary to expectations, a combination of Lap and Cry did not affect the chemoresistance despite the ERα down-regulation; Cry-eIF4A binding possibly dampens this condition. Results indicated the pro-survival eIF4A/STAT/Bcl-xl pathway and that the down-regulation of the MAPK-NF-κB might function as an adaptive mechanism; this response may be compensated by calcium homeostasis in chemoresistance, highlighting new adaptations in HER2+ cells that lead to chemoresistance. Full article

Background: Acute myeloid leukemia (AML), a malignant blood disease, is caused by the excessive growth of undifferentiated myeloid cells, which disrupt normal hematopoiesis and may invade several organs. Given the high heterogeneity in prognosis, identifying stable prognostic biomarkers is crucial for improved risk stratification and personalized treatment strategies. Although glycolysis has been extensively studied in cancer, its prognostic significance in AML remains unclear. Methods: Glycolysis-related prognostic genes were identified by differential expression profiles. We modeled prognostic risk by least absolute shrinkage and selection operator (LASSO) regression and validated it by Kaplan–Meier (KM) survival analysis, receiver operating characteristic (ROC) curves, and independent datasets (BeatAML2.0, GSE37642, GSE71014). Mechanisms were further explored through immune microenvironment analysis and drug sensitivity scores. Results: Differential expression and survival correlation analysis across the genes associated with glycolysis revealed multiple glycolytic genes associated with the outcomes of AML. We constructed a seven-gene prognostic model (G6PD, TFF3, GALM, SOD1, NT5E, CTH, FUT8). Kaplan–Meier analysis demonstrated significantly reduced survival in high-risk patients (hazard ratio (HR) = 3.4, p < 0.01). The model predicted the 1-, 3-, and 5-year survival outcomes, achieving area under the curve (AUC) values greater than 0.8. Immune profiling indicated distinct cellular compositions between risk groups: high-risk patients exhibited elevated monocytes and neutrophils but reduced Th1 cell infiltration. Drug sensitivity analysis showed that high-risk patients exhibited resistance to crizotinib and lapatinib but were more sensitive to motesanib. Conclusions: We established a novel glycolysis-related gene signature for AML prognosis, enabling effective risk classification. Combined with immune microenvironment analysis and drug sensitivity analysis, we screened metabolic characteristics and identified an immune signature to provide deeper insight into AML. Our findings may assist in identifying new therapeutic targets and more effective personalized treatment regimes. Full article

Current antiviral treatments often target specific viral components, which can lead to the rapid emergence of drug-resistant mutants. Targeting host signaling pathways, including their associated cellular factors, that are important for virus replication is a novel approach toward the development of next-generation antivirals to overcome drug resistance. Various cellular receptor tyrosine kinases (RTKs) have previously been shown to play important roles in mediating viral replication including coronaviruses. In this study, we examined the roles of RTKs in SARS-CoV-2 replication in two cell lines, A549-ACE2 (human lung epithelial cells) and Vero-E6 (African Green Monkey kidney cell), via chemical inhibitors. We showed that the HER2 inhibitor Lapatinib significantly reduced viral replication in both cell lines, the TrkA inhibitor GW441756 was effective only in A549-ACE2 cells, while the EGFR inhibitor Gefitinib had little effect in either cell line. Lapatinib and GW441756 exhibited a high therapeutic index (CC₅₀/EC₅₀ > 10) in A549-ACE2 cells. Time-of-addition experiments indicated that Lapatinib may inhibit the early entry step, whereas GW441756 can affect post-entry steps of the viral life cycle. These findings suggest the important roles of HER2 and TrkA signaling in SARS-CoV-2 infection in human lung epithelial cells and support further investigation of RTK inhibitors as potential COVID-19 treatments. Full article

Background/Objective: Cancer is the leading cause of death worldwide despite the diversity of antitumor therapies, which highlights the necessity to explore new anticancer agents. Methods: We synthesized 5,5-diphenylhydantoin derivatives including Schiff’s bases 7–27 and evaluated their cytotoxicity via the MTT assay. Enzymatic inhibition assays, cell cycle and apoptosis analyses, and molecular docking studies were also conducted. Results: Derivative 24 demonstrated the highest cytotoxic activity, with IC₅₀ values of 12.83 ± 0.9 μM, 9.07 ± 0.8 μM, and 4.92 ± 0.3 μM against the cell lines HCT-116, HePG-2, and MCF-7, respectively. Compounds 10, 13, and 21 showed potent antitumor activities versus the examined cell lines (average IC₅₀ = 13.2, 14.5, and 13.1 μM), respectively; moreover, these compounds also demonstrated promising EGFR and HER2 inhibitory activities, with IC₅₀ values in the range 0.28–1.61 µM. Derivative 24 displayed the highest EGFR and HER2 inhibitory activity values (IC₅₀ = 0.07 and 0.04 µM), respectively, which were close to those of the reference drugs erlotinib and lapatinib. Therefore, compound 24 was selected for further examinations and exhibited an inducing effect on apoptosis via diminishing the anti-apoptotic protein levels of BCL-2 (8.598 ± 0.29 ng/mL) and MCL-1 (261.20 ± 8.97 pg/mL) and promoting cell cycle arrest at the G2/M phase (33.46%). The binding relationships between compound 24 and the active sites of EGFR and HER2, which are similar to the co-crystallized inhibitors, were investigated using a molecular docking approach. Conclusions: These findings provide insights into the potential anticancer activities of the synthesized derivatives for further optimization to achieve therapeutic use. Full article

Breast cancer (BC) remains a significant global health challenge due to its complex biology, which complicates both diagnosis and treatment. Immunotherapy and cancer vaccines have emerged as promising alternatives, harnessing the body’s immune system to precisely target and eliminate cancer cells. However, several key factors influence the selection and effectiveness of these therapies, including BC subtype, tumor mutational burden (TMB), tumor-infiltrating lymphocytes (TILs), PD-L1 expression, HER2 resistance, and the tumor microenvironment (TME). BC subtypes play a critical role in shaping treatment responses. Triple-negative breast cancer (TNBC) exhibits the highest sensitivity to immunotherapy, while HER2-positive and hormone receptor-positive (HR+) subtypes often require combination strategies for optimal outcomes. High TMB enhances immune responses by generating neoantigens, making tumors more susceptible to immune checkpoint inhibitors (ICIs); whereas, low TMB may indicate resistance. Similarly, elevated TIL levels are associated with better immunotherapy efficacy, while PD-L1 expression serves as a key predictor of checkpoint inhibitor success. Meanwhile, HER2 resistance and an immunosuppressive TME contribute to immune evasion, highlighting the need for multi-faceted treatment approaches. Current breast cancer immunotherapies encompass a range of targeted treatments. HER2-directed therapies, such as trastuzumab and pertuzumab, block HER2 dimerization and enhance antibody-dependent cellular cytotoxicity (ADCC), while small-molecule inhibitors, like lapatinib and tucatinib, suppress HER2 signaling to curb tumor growth. Antibody–drug conjugates (ADCs) improve tumor targeting by coupling monoclonal antibodies with cytotoxic agents, minimizing off-target effects. Meanwhile, ICIs, including pembrolizumab, restore T-cell function, and CAR-macrophage (CAR-M) therapy leverages macrophages to reshape the TME and overcome immunotherapy resistance. While immunotherapy, particularly in TNBC, has demonstrated promise by eliciting durable immune responses, its efficacy varies across subtypes. Challenges such as immune-related adverse events, resistance mechanisms, high costs, and delayed responses remain barriers to widespread success. Breast cancer vaccines—including protein-based, whole-cell, mRNA, dendritic cell, and epitope-based vaccines—aim to stimulate tumor-specific immunity. Though clinical success has been limited, ongoing research is refining vaccine formulations, integrating combination therapies, and identifying biomarkers for improved patient stratification. Future advancements in BC treatment will depend on optimizing immunotherapy through biomarker-driven approaches, addressing tumor heterogeneity, and developing innovative combination therapies to overcome resistance. By leveraging these strategies, researchers aim to enhance treatment efficacy and ultimately improve patient outcomes. Full article

Background: Despite recent breakthroughs in cancer treatment, non-small cell lung cancer (NSCLC) and breast cancer remain major causes of death from all malignancies. The epidermal growth factor receptor (EGFR) is an important mediator of the pathways involved in cell proliferation, apoptosis, and angiogenesis. Thus, its overexpression triggers several types of cancer, including NSCLC and breast cancer. Methods: In the current study, we synthesized new pyrimidine-tethered compounds (chalcone derivative (B-4), pyrazoline–carbothioamide (B-9), and pyrazoline–thiazole hybrids (BH1-7)). These compounds were then tested for cytotoxicity against A549 NSCLC and MCF-7 breast cancer cells. Results: Of these, B-4 displayed significant cytotoxicity against both cells (IC₅₀ = 6.70 ± 1.02 µM for MCF-7; IC₅₀ = 20.49 ± 2.7 µM for A549) compared to the standard agent lapatinib (IC₅₀ = 9.71 ± 1.12 µM for MCF-7; IC₅₀ = 18.21 ± 3.25 µM for A549). The anticancer potential of B-4 between Jurkat leukemic T cells and peripheral blood mononuclear cells (PBMCs) (healthy) was found to be selective. Mechanistically, 11.9% and 10.2% of A549 and MCF-7 cells treated with B-4, respectively, underwent apoptosis and B-4 produced 46% EGFR inhibition at a concentration of 10 μM. The B-4/EGFR complex obtained after induced fit docking was subjected to 300 ns of molecular dynamics simulation, which confirmed the stability of the complex in a mimicked biological environment. On the other hand, B-4 was shown to have drug-like properties by in silico pharmacokinetic estimation. Conclusions: B-4 is an EGFR inhibitor and apoptosis inducer for future NSCLC and breast cancer studies. Full article

Background: Breast cancer remains a significant global health concern, with approximately 2.3 million diagnosed cases and 670,000 deaths annually. Current targeted therapies face challenges such as resistance and adverse side effects. This study aimed to explore natural compounds as potential multitargeted breast cancer therapeutics, focusing on Lucidin, an anthraquinone derived from Rubia cordifolia, and comparing its efficacy with Lapatinib, an FDA-approved drug. Methods: We performed multitargeted molecular docking studies on key breast cancer proteins using a natural compound library from ZINC. Comparative analyses of Lucidin and Lapatinib included molecular interaction fingerprints, pharmacokinetics, WaterMap computations (5 ns) to assess water thermodynamics and binding interactions, and Molecular Dynamics Simulations (100 ns) in water to evaluate complex stability and dynamic behaviour. Results: Lucidin demonstrated significant binding affinity and interaction potential with multiple breast cancer targets, outperforming Lapatinib in stability and binding interactions. WaterMap analysis revealed favourable hydration site energetics for Lucidin, enhancing its efficacy. The multitargeted profile of Lucidin suggests a broader therapeutic approach with potential to overcome resistance and side effects associated with Lapatinib. Conclusions: Lucidin shows promise as a novel, multitargeted anti-breast cancer agent with improved efficacy over Lapatinib. These findings provide a foundation for further in vitro and in vivo validation to develop Lucidin as a potential therapeutic option for breast cancer treatment. Full article

HER2-positive/oestrogen receptor-positive (HER2+/ER+) represents a unique breast cancer subtype. The use of individual HER2- or ER-targeting agents can lead to the acquisition of therapeutic resistance due to compensatory receptor crosstalk. New drug combinations targeting HER2 and ER could improve outcomes for patients with HER2+/ER+ breast cancer. In this study, the pre-clinical rationale is explored for combining amcenestrant (Amc), a selective oestrogen receptor degrader (SERD), with HER2-targeted therapies including trastuzumab, trastuzumab-emtansine (T-DM1) and tyrosine kinase inhibitors (TKIs). The combination of Amc and anti-HER2 therapies was investigated in a panel of four HER2+/ER+ cell lines: BT-474, MDA-MB-361, EFM-192a and a trastuzumab-resistant variant BT-474-T. Proliferation (IC₅₀ and matrix combination assays) was determined using acid phosphatase assays. HER2/ER and intracellular signalling pathway protein levels/activity were investigated by western blot. Apoptosis was assessed using caspase 3/7 assays. Additivity and synergy were observed between Amc and the TKIs neratinib, lapatinib and tucatinib in all cell lines. Amc increased the anti-proliferative effect of trastuzumab in MDA-MB-361 and BT-474-T. Addition of Amc also increased anti-proliferative efficacy of T-DM1 in BT-474-T. TKI/Amc combinations reduced p-HER2 and ER levels and resulted in increased apoptosis. Higher ER expression in MDA-MB-361 and BT-474-T was associated with greater potential for synergy. In conclusion, the combination of Amc- and HER2-targeted treatments has potential as a therapeutic strategy for the treatment of HER2+/ER+ breast cancer and warrants further clinical investigation to validate safety and efficacy in patients. Full article

Background and Objectives: Metastatic breast cancer (MBC), particularly the HER2-positive subtype, represents a significant clinical challenge, with approximately 20–25% of breast cancer cases demonstrating HER2 overexpression. Trastuzumab, a monoclonal antibody targeting HER2, has significantly improved outcomes in these patients. However, progression after second-line treatments such as trastuzumab emtansine (T-DM1) necessitates exploring subsequent therapeutic options. This study aims to compare the efficacy of trastuzumab plus gemcitabine (GT) with lapatinib plus capecitabine (LC) as third-line treatments in HER2-positive MBC post-T-DM1 failure. Materials and Methods: This retrospective study included 98 HER2-positive MBC patients treated between 2017 and 2023 who progressed after T-DM1. Patients were divided into two groups: 21 received GT, and 28 received LC. Key endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events. Statistical analyses were performed using SPSS 26.0, with Kaplan–Meier survival curves, log-rank tests, and Cox proportional hazards models. Results: Median PFS was significantly longer in the GT group (9.5 months) compared to the LC group (4.3 months, p = 0.02). OS was also higher for GT (22.1 months vs. 10.0 months, p = 0.02). ORR favored the GT group (33.3% vs. 10.7%, p = 0.046), and progressive disease was more common in the LC group (57.1% vs. 33.3%, p = 0.022). The safety profile showed higher rates of diarrhea in the LC group, but both regimens were generally well tolerated. Conclusions: Trastuzumab re-challenge with gemcitabine demonstrated superior PFS, OS, and ORR compared to lapatinib plus capecitabine, suggesting it may be a more effective third-line therapy in HER2-positive MBC patients who have progressed after T-DM1. Further prospective studies are needed to confirm these findings and optimize treatment sequencing. Full article

HER2-positive (HER2+) breast cancer is characterized by the overexpression of the ERBB2 (HER2) gene, which promotes aggressive tumor growth and poor prognosis. Targeting the ERBB2 pathway with single-agent therapies has shown limited efficacy due to resistance mechanisms and the complexity of gene interactions within the tumor microenvironment. This study aims to explore potential drug synergies by analyzing gene–drug interactions and combination therapies that target the ERBB2 pathway in HER2+ breast tumors. Using gene co-expression network analysis, we identified 23 metabolic pathways with significant cross-linking of gene interactions, including those involving EGFR tyrosine kinase inhibitors, PI3K, mTOR, and others. We visualized these interactions using Cytoscape to generate individual and combined drug–gene networks, focusing on frequently used drugs such as Erlotinib, Gefitinib, Lapatinib, and Cetuximab. Individual networks highlighted the direct effects of these drugs on their target genes and neighboring genes within the ERBB2 pathway. Combined drug networks, such as those for Cetuximab with Lapatinib, Cetuximab with Erlotinib, and Erlotinib with Lapatinib, revealed potential synergies that could enhance therapeutic efficacy by simultaneously influencing multiple genes and pathways. Our findings suggest that a network-based approach to analyzing drug combinations provides valuable insights into the molecular mechanisms of HER2+ breast cancer and offers promising strategies for overcoming drug resistance and improving treatment outcomes. Full article

This study evaluates radioiodinated anastrozole ([¹²⁵I]anastrozole) and epirubicin ([¹²⁵I]epirubicin) for HER2-targeted cancer therapy, utilizing radiopharmaceutical therapy (RPT) for personalized treatment of HER2-positive cancers. Through molecular docking and dynamics simulations (200 ns), it investigates these compounds’ binding affinities and mechanisms to the HER2 receptor compared to lapatinib, a known HER2 inhibitor. Molecular docking studies identified [¹²⁵I]epirubicin with the highest ΔG_bind (−10.92 kcal/mol) compared to lapatinib (−10.65 kcal/mol) and [¹²⁵I]anastrozole (−9.65 kcal/mol). However, these differences were not statistically significant. Further molecular dynamics (MD) simulations are required to better understand the implications of these findings on the therapeutic potential of the compounds. MD simulations affirmed a stable interaction with the HER2 receptor, indicated by an average RMSD of 4.51 Å for [¹²⁵I]epirubicin. RMSF analysis pointed to significant flexibility at key receptor regions, enhancing the inhibitory action against HER2. The [¹²⁵I]epirubicin complex maintained an average of four H-bonds, indicating strong and stable interactions. The average Rg values for [¹²⁵I]anastrozole and [¹²⁵I]epirubicin complexes suggest a modest increase in structural flexibility without compromising protein compactness, reflecting their potential to induce necessary conformational changes in the HER2 receptor function. These analyses reveal enhanced flexibility and specific receptor region interactions, suggesting adaptability in binding, which could augment the inhibitory action against HER2. MM-PBSA calculations indicate the potential of these radioiodinated compounds as HER2 inhibitors. Notably, [¹²⁵I]epirubicin exhibited a free binding energy of −65.81 ± 0.12 kJ/mol, which is comparable to lapatinib at −64.05 ± 0.11 kJ/mol and more favorable than [¹²⁵I]anastrozole at −57.18 ± 0.12 kJ/mol. The results suggest electrostatic interactions as a major contributor to the binding affinity. The computational analysis underscores that [¹²⁵I]anastrozole and [¹²⁵I]epirubicin may have a promising role as HER2 inhibitors, especially [¹²⁵I]epirubicin due to its high binding affinity and dynamic receptor interactions. These findings, supported by molecular docking scores and MM-PBSA binding energies, advocate for their potential superior inhibitory capability against the HER2 receptor. To validate these computational predictions and evaluate the therapeutic potential of these compounds for HER2-targeted cancer therapy, it is essential to conduct empirical validation through both in vitro and in vivo studies. Full article

Gastroesophageal adenocarcinoma (GEA) is one of the principal causes of death related to cancer globally. Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor which is found to be overexpressed or amplified in approximately 20% of GEA cases. In GEA, the identification of HER2-positive status is crucial to activate a specific anti-HER2 targeted therapy. The landmark ToGA trial demonstrated the superiority of adding trastuzumab to platinum-based chemotherapy, becoming the first-line standard of treatment. However, unlike breast cancer, the efficacy of other anti-HER2 drugs, such as lapatinib, pertuzumab, and T-DM1, has failed to improve outcomes in advanced and locally advanced resectable GEA. Recently, the combination of trastuzumab with pembrolizumab, along with chemotherapy, and the development of trastuzumab deruxtecan, with its specific bystander activity, demonstrated improved outcomes, renewing attention in the treatment of this disease. This review will summarise historical and emerging therapies for the treatment of HER2-positive GEA, with a section dedicated to the HER2 molecular pathway and the use of novel blood biomarkers, such as circulating tumour DNA and circulating tumour cells, which may be helpful in the future to guide treatment decisions. Full article

Despite a decreasing incidence in Western countries, gastric cancer is among the most common cancer subtypes globally and is associated with one of the highest tumor-related mortality rates. Biomarkers play an increasing role in the treatment against gastric cancer. HER2 was one of the first biomarkers that found its way into clinical practice. Since the ToGA trial, trastuzumab has been part of first-line palliative chemotherapy in metastatic or unresectable gastric cancer. HER2-targeting agents, such as the tyrosine kinase inhibitor lapatinib, the antibody drug conjugate (ADC) trastuzumab-emtansine or dual HER2 inhibition (pertuzumab and trastuzumab), have been investigated in the second-line setting but led to negative study results. More recently, the ADC trastuzumab-deruxtecan was authorized after the failure of trastuzumab-based treatment. However, further improvements in HER2-directed therapy are required as resistance mechanisms and HER2 heterogeneity limit the existing treatment options. This review aims to give an overview of the current standard-of-care HER2-directed therapy in gastric cancer, as well as its challenges and future developments. Full article