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Background: Human epidermal growth factor receptor 2 (HER2)-positive gastric cancer (GC) is a heterogeneous GC subtype characterized by the overexpression of HER2. To date, few specific targeted therapies have demonstrated durable efficacy in HER2-positive GC patients, with resistance to trastuzumab typically emerging within 1 year. However, the mechanisms of resistance to trastuzumab remain incompletely understood, presenting a significant challenge to clinical practice. Methods: In this study, we integrated genetic screening and bulk transcriptome and epigenomic profiling to define the mechanisms mediating adaptive resistance to HER2 inhibitors and identify potential effective therapeutic strategies for treating HER2-positive GCs. Results: We revealed a potential association between adaptive resistance to trastuzumab in HER2-positive GC and the expression of YES-associated protein (YAP). Notably, our investigation revealed that long-term administration of trastuzumab triggers extensive chromatin remodeling and initiates YAP gene transcription in HER2-positive cells characterized by the initial inhibition and subsequent reactivation. Furthermore, treatment of HER2-positive GC cells and cell line-derived xenografts (CDX) models with YAP inhibitors in combination with trastuzumab was found to induce synergistic effects through the AKT/mTOR and ERK/mTOR pathways. Conclusion: These findings underscore the pivotal role of reactivated YAP and mTOR signaling pathways in the development of adaptive resistance to trastuzumab and may serve as a promising joint target to overcome resistance to trastuzumab. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common cancers and is considered the 5th most frequent occurring cancer worldwide. It has gained great attention from the clinicians and researchers because of high mortality rate. It is generally treated with chemotherapy, radiotherapy, and surgery. Recently, additional treatment options including immunotherapy and targeted therapy and immunotherapy have been developed. However, poor prognosis, limited survival rate of patients, and drug resistance to treatment remain critical problems. To improve treatment options or to overcome the bottleneck of treatment, identification of diagnostic and prognostic markers, determining the most effective therapeutic options, and uncovering the molecular regulations associated with treatment strategies are required. In this regard n6 -methyladenosine (m6A) regulation is considered important. This reversible modification plays a crucial role in progression, development and treatment of HER2-positive gastric cancer. Here, we discuss the role of m6A modification in HER2-positive gastric cancer progression through collecting related studies at present. We further discuss the association of m6A modification with therapeutic efficacy in HER2-positive gastric cancer and list some examples. We conclude that modification of m6A can be a new strategy for improving the prognosis and survival rate of HER2-positive gastric cancer patients. [ABSTRACT FROM AUTHOR]

Introduction: Trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of HER2-positive gastric cancer. However, there are only a limited number of cases of gastric cancer where a long-term complete response (CR) has been maintained. Consequently, we report a case of gastric cancer in which long-term CR was maintained. Case Presentation: A woman in her late 60s underwent a gastrointestinal endoscopy, which revealed a type 2 lesion with ulceration in the lesser curvature of the vestibule, and a biopsy, which revealed an adenocarcinoma. Computed tomography (CT) revealed wall thickening of the gastric antecubital region, metastatic liver tumor, and extra-regional lymph node metastasis; a diagnosis of T4a, N3a, M1 (H, LYN), and cStage IVB (HER2 3+) was confirmed. Trastuzumab, oxaliplatin, and S-1 were administered initially. After 9 months, ascites appeared, and progressive disease was diagnosed. Paclitaxel and ramucirumab were started as second-line treatments but discontinued owing to neutropenia and increasing ascites. Third-line treatment with T-Dxd was initiated, and 11 months later, CT showed the disappearance of metastases. Even after 31 months, the CR was maintained. Conclusion: To the best of our knowledge, this is one of the few cases in which long-term CR was maintained with third-line T-Dxd treatment. Treatment strategies for patients with gastric cancer to achieve long-term CR require careful consideration.

Introduction: Trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of HER2-positive gastric cancer. However, there are only a limited number of cases of gastric cancer where a long-term complete response (CR) has been maintained. Consequently, we report a case of gastric cancer in which long-term CR was maintained. Case Presentation: A woman in her late 60s underwent a gastrointestinal endoscopy, which revealed a type 2 lesion with ulceration in the lesser curvature of the vestibule, and a biopsy, which revealed an adenocarcinoma. Computed tomography (CT) revealed wall thickening of the gastric antecubital region, metastatic liver tumor, and extra-regional lymph node metastasis; a diagnosis of T4a, N3a, M1 (H, LYN), and cStage IVB (HER2 3+) was confirmed. Trastuzumab, oxaliplatin, and S-1 were administered initially. After 9 months, ascites appeared, and progressive disease was diagnosed. Paclitaxel and ramucirumab were started as second-line treatments but discontinued owing to neutropenia and increasing ascites. Third-line treatment with T-Dxd was initiated, and 11 months later, CT showed the disappearance of metastases. Even after 31 months, the CR was maintained. Conclusion: To the best of our knowledge, this is one of the few cases in which long-term CR was maintained with third-line T-Dxd treatment. Treatment strategies for patients with gastric cancer to achieve long-term CR require careful consideration. [ABSTRACT FROM AUTHOR]

Background: In the Trastuzumab for Gastric Cancer study, it was found that trastuzumab combined with doublet chemotherapy (fluoropyrimidine and platinum) was the gold‑standard treatment for gastroesophageal adenocarcinoma (GEA) that was locally advanced, unresectable, or metastatic (HER2+). Materials and Methods: We performed a meta‑analysis of randomized phase II/III studies testing trastuzumab in combination or alone. Results: This meta‑analysis’s findings involved 2048 patients in total. The treatment arm and hormone receptor status were used to stratify the combined HR. Overall, the PFS (Random model) HR [0.80] and 95% confidence intervals (CI) [0.68‑0.95] were significantly higher for regimens containing trastuzumab, fluoropyrimidine, and platinum compared to regimens containing fluoropyrimidine and platinum. Conclusions: The results of this meta‑analysis provide additional support for trastuzumab’s use in treating HER2‑positive GEA, particularly in cases where the disease lacks a HER2+ receptor. [ABSTRACT FROM AUTHOR]

Abstract Background We report a case of a patient with HER2-positive gastric cancer with marked tongue swelling during the second cycle of S-1, oxaliplatin, and trastuzumab. Case presentation The patient was a 74-year-old male, who was taking an angiotensin II receptor blocker (ARB) for pre-existing hypertension, with no history of allergies, diagnosed with HER2-positive gastric cancer, treated with tegafur, gimeracil, and oteracil potassium (S-1) and oxaliplatin for the first cycle, and trastuzumab was added from the second cycle. Three weeks after initiation, during an outpatient visit, grade 2 oral mucositis and significant enlargement of the patient's tongue were observed. Due to the risk of airway obstruction, the patient was referred to an otolaryngologist. After examination, hereditary angioedema was ruled out, and treatment was discontinued in view of ARB-induced angioedema. However, the tongue swelling did not improve markedly. Considering disease progression due to the discontinuation of chemotherapy, it was decided to change S-1 to capecitabine and continue treatment, and chemotherapy was resumed. Conclusions Angioedema has been reported to be hereditary and drug-related, and angiotensin-converting enzyme (ACE) inhibitors and ARBs have also been reported to lead to drug-related adverse events. Since the patient had oral mucositis at the time of onset and was taking an ARB, it is thought that oxaliplatin and S-1(SOX), and trastuzumab during ARB therapy induced oral mucositis, leading to the development of angioedema.

Abstract Background Trastuzumab-based chemotherapy is a standard treatment regimen for human epithelial growth factor 2 (HER2)-positive gastric cancer. This is a case of a patient who has survived 12 years after being diagnosed with advanced gastric cancer with multiple liver and lung metastases. Case presentation A woman in her 70s underwent total gastrectomy, cholecystectomy, and left hepatic lobectomy for gastric cancer with liver metastasis. One month after the surgery, multiple liver metastases appeared. After two courses of S-1 + CDDP chemotherapy, the liver metastases disappeared, and new lung metastases occurred. Because the primary tumor was HER2 positive, S-1 + CDDP + trastuzumab chemotherapy was performed. After one course of chemotherapy, the blood test showed pancytopenia, and CDDP was discontinued. S-1 + trastuzumab chemotherapy was then initiated, and as a result, the lung metastases disappeared. The patient is alive without recurrence 12 years after the surgery. Conclusions We encountered a case of long-term survival after multidisciplinary treatments for HER2-positive advanced gastric cancer with multiple liver and lung metastases.

Background: We report a case of a patient with HER2-positive gastric cancer with marked tongue swelling during the second cycle of S-1, oxaliplatin, and trastuzumab. Case presentation: The patient was a 74-year-old male, who was taking an angiotensin II receptor blocker (ARB) for pre-existing hypertension, with no history of allergies, diagnosed with HER2-positive gastric cancer, treated with tegafur, gimeracil, and oteracil potassium (S-1) and oxaliplatin for the first cycle, and trastuzumab was added from the second cycle. Three weeks after initiation, during an outpatient visit, grade 2 oral mucositis and significant enlargement of the patient's tongue were observed. Due to the risk of airway obstruction, the patient was referred to an otolaryngologist. After examination, hereditary angioedema was ruled out, and treatment was discontinued in view of ARB-induced angioedema. However, the tongue swelling did not improve markedly. Considering disease progression due to the discontinuation of chemotherapy, it was decided to change S-1 to capecitabine and continue treatment, and chemotherapy was resumed. Conclusions: Angioedema has been reported to be hereditary and drug-related, and angiotensin-converting enzyme (ACE) inhibitors and ARBs have also been reported to lead to drug-related adverse events. Since the patient had oral mucositis at the time of onset and was taking an ARB, it is thought that oxaliplatin and S-1(SOX), and trastuzumab during ARB therapy induced oral mucositis, leading to the development of angioedema. [ABSTRACT FROM AUTHOR]

Background: HER2 signaling might be involved in the regulation of immune cell activation in the tumor microenvironment (TME) of gastric cancer (GC). However, the relationship between HER2 status and immune cell condition in the HER2-positive GC TME is not clearly understood. Methods: To investigate the effect of HER2 signaling on the activation of the cyclic GMP–AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which contributes to immune cell activation in the GC TME, we evaluated the associations among the expressions of HER2, cGAS–STING, and the number of CD8+ tumor-infiltrating lymphocytes (TIL) by considering HER2 heterogeneity in HER2-positive GC tissues. We also examined the effect of HER2 signaling on the activation of STING signaling in vitro using human HER2-positive GC cell lines. Results: The expression of HER2 is highly heterogeneous in HER2-positive GC tissues, and we found that the number of CD8+ TIL in HER2 high areas was significantly lower than that in HER2 low areas in HER2-positive GC tissues. Intriguingly, the tumor cell-intrinsic expression of STING, but not cGAS, was also significantly lower in the HER2 high areas than the HER2 low areas in HER2-positive GC tissues. Moreover, in vitro experiments, we demonstrated that the blockade of HER2 signaling increased the expression of STING and its target genes, including IFNB1, CXCL9/10/11, and CCL5, in HER2-positive GC cell lines. Conclusions: Our results suggest that HER2 signaling might suppress immune cell activation in the GC TME by inhibiting STING signaling in tumor cells in HER2-positive GC. [ABSTRACT FROM AUTHOR]

Abstract Background We aimed to determine the molecular and immune microenvironment characteristics of HER2‐positive gastric cancer (GC) related to the patient's response to first‐line trastuzumab‐based treatment. Methods Eighty‐three cases of HER2‐positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post‐treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor‐infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression‐free survival (PFS) analysis was performed. Results Group 1 showed frequent amplification of G1/S cell cycle checkpoint‐related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune‐related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle‐related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p

Background: Trastuzumab-based chemotherapy is a standard treatment regimen for human epithelial growth factor 2 (HER2)-positive gastric cancer. This is a case of a patient who has survived 12 years after being diagnosed with advanced gastric cancer with multiple liver and lung metastases. Case presentation: A woman in her 70s underwent total gastrectomy, cholecystectomy, and left hepatic lobectomy for gastric cancer with liver metastasis. One month after the surgery, multiple liver metastases appeared. After two courses of S-1 + CDDP chemotherapy, the liver metastases disappeared, and new lung metastases occurred. Because the primary tumor was HER2 positive, S-1 + CDDP + trastuzumab chemotherapy was performed. After one course of chemotherapy, the blood test showed pancytopenia, and CDDP was discontinued. S-1 + trastuzumab chemotherapy was then initiated, and as a result, the lung metastases disappeared. The patient is alive without recurrence 12 years after the surgery. Conclusions: We encountered a case of long-term survival after multidisciplinary treatments for HER2-positive advanced gastric cancer with multiple liver and lung metastases. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the molecular and immune microenvironment characteristics of HER2‐positive gastric cancer (GC) related to the patient's response to first‐line trastuzumab‐based treatment. Methods: Eighty‐three cases of HER2‐positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post‐treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor‐infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression‐free survival (PFS) analysis was performed. Results: Group 1 showed frequent amplification of G1/S cell cycle checkpoint‐related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune‐related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle‐related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune‐related including high density of CD3−CD57+ NK cells and PD‐L1 combined positive score ≥5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001). Conclusion: HER2‐positive GC with favorable response to trastuzumab were characterized by cell cycle‐related gene alterations and increased CD3−CD57+ NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2‐positive GC. [ABSTRACT FROM AUTHOR]

Abstract Background Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear. Methods Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies. Results Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM–1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p

Synchronous occurrences of gastric cancer positive for human epidermal growth factor receptor 2 (HER2+) and bladder cancer are rarely encountered in clinical practice. When and how to effectively treat both tumors, without compounding adverse effects, must be addressed. Herein, we describe an elderly man who presented with both gastric cancer (HER2+) and bladder cancer. Due to enlarged and fused lymph nodal metastasis, he was ill-suited for stomach resection. After transurethral resection of the bladder tumor, we administered both chemotherapy and the targeted agent trastuzumab. Gastric cancer showed partial response however bladder cancer recurred following two cycles of this regimen, the adverse effects were prohibitive, prompting refusal of further chemotherapy and radiotherapy. He then received the immune checkpoint inhibitor (ICI) nivolumab and trastuzumab in combination. This particular regimen successfully controlled both cancers and substantially improved the patient's quality of life. Its long-term use did not intensify adverse reactions, enabling a progression-free survival of 21 months to date. We have also reviewed other published clinical strategies applied in rare instances of multiple primary malignancies as a reference for treating such patients. [ABSTRACT FROM AUTHOR]

Background: Aberrant PI3K signalling is implicated in trastuzumab resistance in HER2-positive gastric cancer (GC). The role of PI3K or MEK inhibitors in sensitising HER2-positive GCs to trastuzumab or in overcoming trastuzumab resistance is unclear.Methods: Using mass spectrometry-based genotyping we analysed 105 hotspot, non-synonymous somatic mutations in PIK3CA and ERBB-family (EGFR, ERBB2, ERBB3 and ERBB4) genes in gastric tumour samples from 69 patients. A panel of gastric cell lines (N87, OE19, ESO26, SNU16, KATOIII) were profiled for anti-proliferative response to the PI3K inhibitor copanlisib and the MEK1/2 inhibitor refametinib alone and in combination with anti-HER2 therapies.Results: Patients with HER2-positive GC had significantly poorer overall survival compared to HER2-negative patients (15.9 months vs. 35.7 months). Mutations in PIK3CA were only identified in HER2-negative tumours, while ERBB-family mutations were identified in HER2-positive and HER2-negative tumours. Copanlisib had anti-proliferative effects in 4/5 cell lines, with IC50s ranging from 23.4 (N87) to 93.8 nM (SNU16). All HER2-positive cell lines except SNU16 were sensitive to lapatinib (IC50s 0.04 µM-1.5 µM). OE19 cells were resistant to trastuzumab. The combination of lapatinib and copanlisib was synergistic in ESO-26 and OE-19 cells (ED50: 0.83 ± 0.19 and 0.88 ± 0.13, respectively) and additive in NCI-N87 cells (ED50:1.01 ± 0.55). The combination of copanlisib and trastuzumab significantly improved growth inhibition compared to either therapy alone in NCI-N87, ESO26 and OE19 cells (p < 0.05).Conclusions: PI3K or MEK inhibition alone or in combination with anti-HER2 therapy may represent an improved treatment strategy for some patients with HER2-positive GC, and warrants further investigation in a clinical trial setting. [ABSTRACT FROM AUTHOR]

Gastric cancer is one of the most common cancers and is considered the 5 th most frequent occurring cancer worldwide. It has gained great attention from the clinicians and researchers because of high mortality rate. It is generally treated with chemotherapy, radiotherapy, and surgery. Recently, additional treatment options including immunotherapy and targeted therapy and immunotherapy have been developed. However, poor prognosis, limited survival rate of patients, and drug resistance to treatment remain critical problems. To improve treatment options or to overcome the bottleneck of treatment, identification of diagnostic and prognostic markers, determining the most effective therapeutic options, and uncovering the molecular regulations associated with treatment strategies are required. In this regard n 6 -methyladenosine (m6A) regulation is considered important. This reversible modification plays a crucial role in progression, development and treatment of HER2 -positive gastric cancer. Here, we discuss the role of m6A modification in HER2 -positive gastric cancer progression through collecting related studies at present. We further discuss the association of m6A modification with therapeutic efficacy in HER2 -positive gastric cancer and list some examples. We conclude that modification of m6A can be a new strategy for improving the prognosis and survival rate of HER2 -positive gastric cancer patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jia, Zhang, Zeng, Wu, Tian and Xing.)

Background/aim: Intra-tumoral heterogeneity, which is frequently found in various types of cancers, has been suggested to play an important role in cancer progression and metastasis. The findings of our previous study suggested that p-SMAD2 and c-MET signaling might play important roles in the progression to lymph node metastasis of HER2-positive gastric cancer. In this study, we confirmed the effect of SMAD2/MET signaling in the progression of HER2-positive gastric cancer in an animal model., Materials and Methods: NCI-N87 cells over-expressing ERBB2, SMAD2, MET were used. To confirm the role of SMAD2 and MET expression on lymph node metastasis of gastric cancer, we orthotopically injected NCI-N87 cells with or without the knockdown of both SMAD2 and MET into the gastric walls of BALBc nude mice., Results: The number of metastatic lymph nodes was significantly smaller in the knockdown group compared to that in the control group. However, there was no significant difference in gastric tumor size between the two groups., Conclusion: SMAD2 and MET signaling might play important roles specifically in the progression to lymph node metastasis of HER2-positive gastric cancer. c-MET and SMAD2 may be useful targets for preventing lymph node metastasis in patients with HER2-positive gastric cancer., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Antibody drug conjugates (ADCs) have shown promise to be the mainstream chemotherapeutics for advanced HER2-positive cancers, yet the issues of poor drug delivery efficiency, limited chemotherapeutic effects, severe immune responses, and drug resistance remain to be addressed before the clinical applications of ADCs. The DNA aptamer-guided drug conjugates (ApDCs) are receiving growing attention for specific tumors due to their excellent tumor affinity and low cost. Therefore, developing a multivalent ApDC nanomedicine by combining anti-HER2 aptamer (HApt), tetrahedral framework nucleic acid (tFNA), and deruxtecan (Dxd) together to form HApt-tFNA@Dxd might help to address these concerns. In this study, the HER2-targeted DNA aptamer modified DNA tetrahedron (HApt-tFNA) was employed as a system for drug delivery, and the adoption of tFNA could effectively enlarge the drug-loading rate compared to aptamer-guided ApDCs previously reported. Compared with free Dxd and tFNA@Dxd, HApt-tFNA@Dxd showed better structural stability, excellent targeted cytotoxicity to HER2-positive gastric cancer, and increased tissue aggregation ability in tumors. These features and superiorities make HApt-tFNA@Dxd a promising chemotherapeutic medicine for HER2-positive tumors. Our work developed a new targeting nanomedicine by combining DNA nanomaterials and chemotherapeutic agents, which represents a critical advance toward developing novel DNA-based nanomaterials and promoting their potential applications for HER2-positive cancer therapy.

Background: Combination chemotherapy with trastuzumab and cisplatin plus capecitabine or 5-fluorouracil has been used as a standard regimen for HER2-positive gastric cancer (GC) since the Trastuzumab for Gastric Cancer (ToGA) trial. Before the ToGA trial, HER2-positive GC in Japan was treated with S-1 plus cisplatin (SP). The primary objective of this retrospective study was to explore the efficacy of SP in HER2-positive GC. Methods: We reviewed patients who had received SP as first-line chemotherapy at our institute between April 2007 and March 2011 and from whom we had enough samples to examine HER2 status. Seventy-seven patients fulfilled the selection criteria and were tested for HER2 status with immunohistochemical staining (IHC) and fluorescence in situ hybridization. The patients' backgrounds were investigated to evaluate the clinicopathologic features of their HER2-positive GC, including survival. Results: Seven (9.1 %) of 77 patients were judged to be IHC3+, and all of these had predominantly differentiated histology. HER2 positivity was associated with differentiated histology ( P = 0.016) and liver metastasis ( P = 0.025). Median overall survival was 23.6 months [95 % confidence interval (CI) 0.8-44.7] in HER2-positive GC and 12.9 months (95 % CI 8.3-17.5) in HER2-negative disease, but the difference was not statistically significant ( P = 0.615). In multivariate analysis, HER2 status was not associated with survival outcomes. Conclusion: Because of the retrospective nature of this study, we cannot conclude whether HER2 status influences the survival of patients who receive SP as first-line chemotherapy. Our study provides important historical data for prospective phase II studies of SP plus trastuzumab. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab (Tmab) resistance is a major clinical problem to be resolved in patients with HER2-positive gastric cancers. However, in contrast to the situation for HER2-positive breast cancer lines, the Tmab-resistant gastric cancer preclinical models that are needed to develop a new therapy to overcome this problem are not yet available. Methods: We developed three new cell lines from HER2 gene-amplified gastric cancer cell lines (GLM-1, GLM-4, NCI N-87) by a new in vivo selection method consisting of the repeated culture of small residual peritoneal metastasis but not subcutaneous tumor after Tmab treatment. We then evaluated the anti-tumor efficacy of lapatinib for these Tmab-resistant cells. Results: We successfully isolated two Tmab-resistant cell lines (GLM1-HerR2(3), GLM4-HerR2) among the three tested cell lines. These resistant cells differed from the parental cells in their flat morphology and rapid growth in vitro, but HER2, P95HER2 expression, and Tmab binding were essentially the same for the parental and resistant cells. MUC4 expression was up- or downregulated depending on the cell line. These resistant cells were still sensitive to lapatinib, similar to the parental cells, in vitro. This growth inhibition of the Tmab-resistant cells by lapatinib was due to both G1 cell-cycle arrest and apoptosis induction via effective blockade of the PI3K/Akt and MAPK pathways. A preclinical study confirmed that the Tmab-resistant tumors are significantly susceptible to lapatinib. Conclusion: These results suggest that lapatinib has antitumor activity against the Tmab-resistant gastric cancer cell lines, and that these cell lines are useful for understanding the mechanism of Tmab resistance and for developing a new molecular therapy for Tmab-resistant HER2-positive gastric cancers. [ABSTRACT FROM AUTHOR]

Trastuzumab combined with chemotherapy is the first-line treatment for advanced HER2-positive gastric cancer, but it still suffers from limited therapeutic efficiency and serious side effects, which are usually due to the poor delivery efficiency and the drug resistance of tumor cells to the chemotherapeutic drugs. Herein, a type of ultrasound microbubble for simultaneous delivery of sonosensitizers and therapeutic antibodies to achieve targeting combination of sonodynamic therapy and antibody therapy of HER2-positive gastric cancer was constructed from pyropheophorbide-lipid followed by trastuzumab conjugation (TP MBs). In vitro and in vivo studies showed that TP MBs had good biological safety, and their in vivo delivery can be monitored by ultrasound/fluorescence bimodal imaging. With ultrasound (US) located at the tumor area, TP MBs can be converted into nanoparticles (TP NPs) in situ by US-targeted microbubble destruction; plus the enhanced permeability and retention effects and the targeting effects of trastuzumab, the enrichment of sonosensitizers and antibodies in the tumor tissue can be greatly enhanced (∼2.1 times). When combined with ultrasound, TP MBs can not only increase the uptake of sonosensitizers in HER2-positive gastric cancer NCI-N87 cells but also efficiently generate singlet oxygen to greatly increase the killing effect on cells, obviously inhibiting the tumor growth in HER2-positive gastric cancer NCI-N87 cell models with a tumor inhibition rate up to 79.3%. Overall, TP MBs combined with US provided an efficient way for co-delivery of sonosensitizers and antibodies, greatly enhancing the synergistic therapeutic effect on HER2-positive gastric cancer while effectively reducing the side effects.

Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the most common cancers worldwide. In the clinical setting, the identification of HER2 overexpression in GC was a significant finding, as trastuzumab, an anti-HER2 drug, provides a survival advantage to HER2-positive GC patients. In HER2-postive GC, the dysregulation of PI3K/AKT and MAPK/ERK signaling pathways has been reported, and inhibition of these pathways is an important therapeutic strategy. MiR-143 is known to act as a tumor suppressor in several cancers, such as bladder cancer, breast cancer, colorectal cancer, and gastric cancer. In the current study, we developed a novel chemically-modified miR-143 and explored the functions of this synthetic miR-143 (syn-miR-143) in HER2-positive gastric cancer. The expression level of miR-143 was down-regulated in GC cell lines, including HER2-positive GC cell lines, MKN7, and KATO-III. The ectopic expression of miR-143 in those cell lines suppressed cell growth through systemic silencing of KRAS and its effector signaling molecules, AKT and ERK. Furthermore, syn-miR-143 indirectly down-regulated the expression of HER2, an upstream molecule of KRAS, through silencing DEAD/H-box RNA helicase 6 (DDX6), RNA helicase, which enhanced HER2 protein expression at the translational step in HER2-positive GC cells. These findings suggested that syn-miR-143 acted as a tumor suppressor through the impairment of KRAS networks including the DDX6.

Several agents that target specific molecules have been investigated for the treatment of gastric cancer in many preclinical and clinical studies. Anti-HER2 antibody, when combined with classical cytotoxic agents, has been shown to confer a significant survival benefit in patients with HER2-positive gastric cancer. This is the only targeted drug that has been shown to be successful for the treatment of gastric cancer. We need to determine specific targets for regulating gastric cancer cells by translational research, develop precise diagnostic procedures for personalized medicine, and identify candidate drugs for gastric cancer.