Sorafenib plus triplet therapy with venetoclax, azacitidine and homoharringtonine for refractory/relapsed acute myeloid leukemia with FLT3-ITD: A multicenter phase 2 study.

BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.

Impact of genetic patterns on sorafenib efficacy in patients with FLT3-ITD acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation: a multi-center, cohort study.

Sorafenib therapy improves overall survival (OS) in patients with FLT3 internal tandem duplication (ITD) acute myeloid leukemia (AML) undergoing allogeneic hematopoietic stem cell transplantation. We explored the efficacy of sorafenib therapy in this population with different concomitant genetic patterns. In this multi-center, cohort study, we enrolled patients with FLT3-ITD AML undergoing allogenic hematopoietic cell transplantation. Patients with sorafenib maintenance post-transplantation for at least four weeks were allocated to the sorafenib group, and otherwise to the control group. Endpoints were OS, disease-free survival, and relapse for the whole cohort and OS for genetic pattern subgroups. Among 613 patients enrolled, 275 were in the sorafenib and 338 the control group. Median follow-up was 36.5 (interquartile range (IQR), 25.2-44.7) months post-transplantation. The 3-year OS post-transplantation was 79.6% (95% confidential interval (CI) 74.8%-84.6%) and 65.2% (95% CI 60.3%-70.6%) (Hazard ratio (HR) 0.50, 95% CI 0.37-0.69; P < 0.0001) in both groups. Sorafenib maintenance post-transplantation improved OS in the favorable (HR 0.33, 95% CI 0.14-0.77; P = 0.011) and adverse (HR 0.56, 95% CI 0.33-0.93; P = 0.026) ELN 2017 risk subgroups. Patients with mutated NPM1, DNMT3A, co-occurring NPM1/DNMT3A, "activated signaling" and "DNA methylation" genes benefited in OS from sorafenib maintenance, while those carrying CEBPA, "tumor suppressors" and "myeloid transcription factors" genes did not. Patients with FLT3-ITDhigh and FLT3-ITDlow AML both benefited in OS from sorafenib maintenance. Our results identify the response of genetic patterns to sorafenib maintenance, providing new viewpoints for the optimal use of sorafenib in FLT3-ITD AML in the transplantation setting.

Nestin+ Mesenchymal Stromal Cells Fibrotic Transition Mediated by CD169+ Macrophages in Bone Marrow Chronic Graft-versus-Host Disease.

Chronic graft-versus-host disease (cGVHD) involves multiple organs, but little is known about bone marrow (BM) alterations caused by cGVHD. In mice and humans, we found that cGVHD is associated with BM fibrosis resulting in T cell infiltration, IgG deposition, and hematopoietic dysfunction. Macrophages and Nestin+ mesenchymal stromal cells (MSCs) participated in the process of BM fibrosis during BM cGVHD development. BM macrophage numbers were significantly increased in mice and humans with BM fibrosis associated with cGVHD. Amplified macrophages produced TGF-ß1, which recruited Nestin+ MSCs forming clusters, and Nestin+ MSCs later differentiated into fibroblasts, a process mediated by increased TGF-ß/Smad signaling. TLR4/MyD88-mediated activation of endoplasmic reticulum (ER) stress in macrophages is associated with fibrosis by increasing Nestin+ MSC migration and differentiation into fibroblasts. Depletion of macrophages by clodronate-containing liposomes and inhibition of ER stress by 4-phenylbutyric acid reversed BM fibrosis by inhibiting fibroblast differentiation. These studies provide insights into the pathogenesis of BM fibrosis during cGVHD development.

Ruxolitinib versus basiliximab for steroid-refractory acute graft-versus-host disease: a retrospective study.

Acute graft-versus-host disease (aGVHD) remains a major limitation of allogeneic hematopoietic stem cell transplantation; not all patients respond to standard glucocorticoids treatment. This study retrospectively evaluated the effects of ruxolitinib compared with basiliximab for steroid-refractory aGVHD (SR-aGVHD). One hundred and twenty-nine patients were enrolled, 81 in ruxolitinib and 48 in basiliximab group. The overall response (OR) at day 28 was higher in ruxolitinib group (72.8% vs. 54.2%, P = 0.031), as with complete response (CR) (58.0% vs. 35.4%, P = 0.013). Ruxolitinib led to significantly lower 1-year cumulative incidence of chronic GVHD (cGVHD) (29.6% vs. 43.8%, P = 0.021). Besides, ruxolitinib showed higher 1-year overall survival (OS) and 1-year cumulative incidence of failure-free survival (FFS) (OS: 72.8% vs. 50.0%, P = 0.008; FFS: 58.9% vs. 39.6%, P = 0.014). The 1-year cumulative incidence of non-relapse mortality (NRM) was lower in ruxolitinib group (16.1% vs. 37.5%, P = 0.005), and the 1-year relapse was not different. The 1-year cumulative incidence of cytomegalovirus (CMV) viremia, CMV-associated diseases and Epstein-Barr virus (EBV)-associated diseases was similar between the two groups, but EBV viremia was significantly lower in ruxolitinib group (6.2% vs. 29.2%, P < 0.001). Subgroup analyses revealed that OR and survival were similar in ruxolitinib 5 mg twice daily (bid) and 10 mg bid groups. However, ruxolitinib 10 mg bid treatment markedly reduced 1-year cumulative incidence of cGVHD compared with 5 mg bid (21.1% vs. 50.0%, P = 0.016). Our study demonstrated that ruxolitinib was superior to basiliximab in SR-aGVHD treatment and cGVHD prophylaxis, therefore should be recommended.

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial.

BACKGROUND: Our open-label, multicentre, randomised, phase 3 trial showed that sorafenib maintenance after haematopoietic stem-cell transplantation (HSCT) improved overall survival and reduced relapse for patients with FLT3 internal tandem duplication (FLT3-ITD) acute myeloid leukaemia undergoing allogeneic HSCT. Here, we present a post-hoc analysis on the 5-year follow-up data of this trial. METHODS: This phase 3 trial, done in seven hospitals in China, included patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT, who were aged 18-60 years, had an Eastern Cooperative Oncology Group performance status of 0-2, had composite complete remission before and after transplantation, and had haematopoietic recovery within 60 days after transplantation. Patients were randomly assigned (1:1) to receive sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30-60 days after transplantation. Randomisation was done with permuted blocks (block size four) via an interactive web-based system. Investigators and participants were not masked to group assignment. The primary endpoint was the 1-year cumulative incidence of relapse, which was reported previously. For this updated analysis, the 5-year endpoints were overall survival; cumulative incidence of relapse; non-relapse mortality; leukaemia-free survival; graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS); cumulative incidence of chronic GVHD; and late effects in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02474290, and is complete. FINDINGS: Between June 20, 2015, and July 21, 2018, 202 patients were randomly assigned to sorafenib maintenance (n=100) or non-maintenance (n=102). Median follow-up was 60·4 months (IQR 16·7-73·3). Extended follow-up showed improved overall survival (72·0% [95% CI 62·1-79·7] vs 55·9% [45·7-64·9]; hazard ratio [HR] 0·55, 95% CI 0·34-0·88; p=0·011), leukaemia-free survival (70·0% [60·0-78·0] vs 49·0% [39·0-58·3]; 0·47, 0·30-0·73; p=0·0007), and GRFS (58·0% [47·7-67·0] vs 39·2% [29·8-48·5]; 0·56, 0·38-0·83; p=0·0030), lower cumulative incidence of relapse (15·0% [8·8-22·7] vs 36·3% [27·0-45·6]; 0·33, 0·18-0·60; p=0·0003), and no increase in non-relapse mortality (15·0% [8·8-22·7] vs 14·7% [8·6-22·3]; 0·79, 0·39-1·62; p=0·98) for patients in the sorafenib group compared with those in the control group. The 5-year cumulative incidence of chronic GVHD (54·0% [43·7-63·2] vs 51·0% [40·8-60·3]; 0·82, 0·56-1·19; p=0·73) did not differ significantly between the two groups and we did not find substantial differences in late effects between the two groups. There were no treatment-related deaths. INTERPRETATION: With extended follow-up, sorafenib maintenance after transplantation is associated with improved long-term survival and reduced relapse rates compared with non-maintenance, further supporting this strategy as a standard of care for patients with FLT3-ITD acute myeloid leukaemia undergoing allogeneic HSCT. FUNDING: None. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Venetoclax Combined with Azacitidine and Homoharringtonine in Relapsed/Refractory AML: A Multicenter, Phase 2 Trial.

BACKGROUND: Relapsed or refractory acute myeloid leukemia (R/R AML) has a dismal prognosis. The aim of this study was to investigate the activity and tolerability of venetoclax combined with azacitidine plus homoharringtonine (VAH) regimen for R/R AML. METHODS: This phase 2 trial was done at ten hospitals in China. Eligible patients were R/R AML (aged 18-65 years) with an Eastern Cooperative Oncology Group performance status of 0-2. Patients received venetoclax (100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14) and azacitidine (75 mg/m2 on days 1-7) and homoharringtonine (1 mg/m2 on days 1-7). The primary endpoint was composite complete remission rate [CRc, complete response (CR) plus complete response with incomplete blood count recovery (CRi)] after 2 cycles of treatment. The secondary endpoints include safety and survival. RESULTS: Between May 27, 2020, and June 16, 2021, we enrolled 96 patients with R/R AML, including 37 primary refractory AML and 59 relapsed AML (16 relapsed after chemotherapy and 43 after allo-HSCT). The CRc rate was 70.8% (95% CI 60.8-79.2). In the patients with CRc, measurable residual disease (MRD)-negative was attained in 58.8% of CRc patients. Accordingly, overall response rate (ORR, CRc plus partial remission (PR)) was 78.1% (95% CI 68.6-85.4). At a median follow-up of 14.7 months (95% CI 6.6-22.8) for all patients, median overall survival (OS) was 22.1 months (95% CI 12.7-Not estimated), and event-free survival (EFS) was 14.3 months (95% CI 7.0-Not estimated). The 1-year OS was 61.5% (95% CI 51.0-70.4), and EFS was 51.0% (95% CI 40.7-60.5). The most common grade 3-4 adverse events were febrile neutropenia (37.4%), sepsis (11.4%), and pneumonia (21.9%). CONCLUSIONS: VAH is a promising and well-tolerated regimen in R/R AML, with high CRc and encouraging survival. Further randomized studies are needed to be explored. Trial registration clinicaltrials.gov identifier: NCT04424147.

Genetic characteristics predict response to venetoclax plus hypomethylating agents in relapsed or refractory acute myeloid leukemia.

BACKGROUND: The heterogeneity of relapsed or refractory (R/R) acute myeloid leukemia (AML) leads to no response to venetoclax (VEN)-based therapy in more than half of the patients. Genetic characteristics are considered important predictors for response to treatment in adults with AML. However, the association of genetic characteristics with outcomes receiving VEN-based therapy is incompletely understood in R/R AML. OBJECTIVE: To evaluate the efficacy of VEN combined with hypomethylating agents (HMA) and identify the potential genetic predictors of response in R/R AML. METHODS: A total of 150 R/R AML patients treated with VEN combined with HMA were enrolled in this retrospective study. Outcomes of the response and overall survival (OS) were analyzed. The predictors of response and OS were analyzed by logistic regression or Cox proportional hazards model. RESULTS: With a median of two (range, 1-4) cycles of therapy, the overall response rate was 56.2%, including 22.0% complete remission (CR), 21.3% CR with incomplete hematologic recovery, 2.0% morphologic leukemia-free state, and 10.7% partial remission, in which 25 patients achieved measurable residual disease (MRD)-negative response. With a median follow-up of 11.2 [95% confidence interval (CI), 7.2-14.8] months, 1- and 2-year OS were 46.9% (95% CI, 37.8%-58.1%) and 38.9% (95% CI, 28.7%-52.9%), respectively. Adverse cytogenetics and European Leukemia Net (ELN) risk predicted inferior response to VEN-based therapy. Mutations in IDH1/2, NPM1, ASXL1, and chromatin-cohesin genes predicted superior response to VEN-based therapy, whereas mutations in active signaling genes such as FLT3-ITD and K/NRAS predicted inferior response. CONCLUSION: VEN combined with HMA was effective with R/R AML patients, and the response to treatment was associated with genetic characteristics.

The Presence of Ascites Affects the Predictive Value of HVPG on Early Rebleeding in Patients with Cirrhosis.

BACKGROUND AND AIMS: Gastroesophageal variceal bleeding is a serious complication of portal hypertension in cirrhotic patients and could be predicted by hepatic venous pressure gradient (HVPG). However, whether the presence of ascites affects the prognostic value of HVPG for patients with acute variceal bleeding is still unknown. This retrospective study is aimed at investigating the influence of ascites on predictive performance of HVPG for early rebleeding in cirrhotic patients with acute variceal bleeding. METHODS: In this retrospective study, a total of 148 patients with cirrhosis hospitalized for acute variceal bleeding who underwent HVPG measurement and endoscopic variceal ligation (EVL) for the prevention of rebleeding were included. The receiver operating characteristic curve (ROC) and logistical regression method were employed to analyze the predictive performance of HVPG for early rebleeding. The locally weighted scatterplot smoothing approach was adopted to assess the monotonicity between bleeding risk and HVPG. RESULTS: A significantly higher HVPG level was observed in patients with early rebleeding compared to patients without rebleeding in the nonascites cohort. When using HVPG to predict early rebleeding, there was a lower area under curve in the ascites cohort compared to the nonascites cohort. HVPG was recognized as a risk factor for early rebleeding by a logistic regression model only in the nonascites cohort. An overall monotonicity in the trend of change in HVPG and risk for early rebleeding was observed in the nonascites cohort solely. CONCLUSION: The predictive value of HVPG for early rebleeding in patients with cirrhosis that developed acute variceal bleeding is hindered by the presence of ascites.

Hepatic venous pressure gradient-guided laparoscopic splenectomy and pericardial devascularisation versus endoscopic therapy for secondary prophylaxis for variceal rebleeding in portal hypertension (CHESS1803): study protocol of a multicenter randomised controlled trial in China.

INTRODUCTION: Gastro-oesophageal variceal bleeding is one of the most common and severe complications with high mortality in cirrhotic patients who developed portal hypertension. Hepatic venous pressure gradient (HVPG) is a globally recommended golden standard for the portal pressure assessment and an HVPG ≥16 mm Hg indicates a higher risk of death and rebleeding. This study aims to compare the effectiveness and safety of splenectomy and pericardial devascularisation (laparoscopic therapy) plus propranolol and endoscopic therapy plus propranolol for variceal rebleeding in cirrhotic patients with HVPG between 16 and 20 mm Hg. METHODS AND ANALYSIS: This is a multicenter, randomised, controlled clinical trial. Participants will be 1:1 assigned randomly into either laparoscopic or endoscopic groups. Forty participants whose transjugular HVPG lies between 16 and 20 mm Hg with a history of gastro-oesophageal variceal bleeding will be recruited from three sites in China. Participants will receive either endoscopic therapy plus propranolol or laparoscopic therapy plus propranolol. The primary outcome measure will be the occurrence of gastro-oesophageal variceal rebleeding. Secondary outcome measures will include overall survival, occurrence of hepatocellular carcinoma, the occurrence of venous thrombosis, the occurrence of adverse events, quality of life and tolerability of treatment. Outcome measures will be evaluated at baseline, 12 weeks, 24 weeks, 36 weeks, 48 weeks and 60 weeks. Multivariate COX regression model will be introduced for analyses of occurrence data and Kaplan-Meier analysis with the log-rank test for intergroup comparison. ETHICS AND DISSEMINATION: Ethical approval was obtained from all three participating sites. Primary and secondary outcome data will be submitted for publication in peer-reviewed journals and widely disseminated. TRIAL REGISTRATION NUMBER: NCT03783065; Pre-results. TRIAL STATUS: Recruitment for this study started in December 2018 while the first participant was randomised in January 2019. Recruitment is estimated to stop in October 2019.

The predictive value of baseline hepatic venous pressure gradient for variceal rebleeding in cirrhotic patients receiving secondary prevention.

BACKGROUND: Baseline hepatic venous pressure gradient (HVPG) has been applied for prediction of variceal rebleeding in patients after acute variceal bleeding. However, for patients receiving secondary prevention, there still lacks evidence about the predictive performance of baseline-HVPG for rebleeding. This study aims to investigate the predictive value of baseline-HVPG for variceal rebleeding in cirrhotic patients receiving secondary prevention. METHODS: This retrospective study included 122 patients with cirrhosis accepting secondary prevention of variceal rebleeding in a university hospital. All the included patients had HVPG measurements before rebleeding and had at least 1-year follow-up after HVPG measurement unless the rebleeding occurred. The rebleeding rate in patients with different HVPG levels and time-dependent predictive performance of baseline-HVPG were analysed. A Cox regression model and P for trend were used to assess the rebleeding risk. RESULTS: Variceal rebleeding occurred in 22 (18.0%) patients during 1-year follow-up. No significant difference was observed in rebleeding rate between patients with HVPG <16 mmHg and HVPG ≥16 mmHg (17.91% vs. 26.41%, P=0.200). A decreasing trend was observed in area under the curve of HVPG for predicting rebleeding by time. The multivariate Cox model showed an overall decreasing trend in hazard ratio of rebleeding (vs. patients with HVPG <12 mmHg) for patients with 12≤ HVPG <16 mmHg, 16≤ HVPG <20 mmHg and HVPG ≥20 mmHg; besides, an increasing P for trend was observed. CONCLUSIONS: A single baseline-HVPG measurement was insufficient for predicting rebleeding in patients with cirrhosis who received secondary prevention.

PITPNC1 fuels radioresistance of rectal cancer by inhibiting reactive oxygen species production.

BACKGROUND: Neoadjuvant radiotherapy is a commonly used method for the current standard-of-care for most patients with rectal cancer, when the effects of radioresistance are limited. The phosphatidylinositol transfer protein, cytoplasmic 1 (PITPNC1), a lipid-metabolism-related gene, has previously been proved to manifest pro-cancer effects in multiple types of cancer. However, whether PITPNC1 plays a role for developing radioresistance in rectal cancer patients is still unknown. Therefore, this study aims to investigate the role of PITPNC1 in rectal cancer radioresistance. METHODS: Patient-derived tissue were used to detect the difference in the expression level of PITPNC1 between radioresistant and radiosensitive patients. Bioinformatic analyses of high-throughput gene expression data were applied to uncover the correlations between PITPNC1 level and oxidative stress. Two rectal cancer cell lines, SW620, and HCT116, were selected in vitro to investigate the effect of PITPNC1 on radioresistance, reactive oxygen species (ROS) generation, apoptosis, and proliferation in rectal cancer. RESULTS: PITPNC1 is highly expressed in radioresistant patient-derived rectal cancer tissues compared to radiosensitive tissue; therefore, PITPNC1 inhibits the generation of ROS and improves the extent of radioresistance of rectal cancer cell lines and then inhibits apoptosis. Knocking down PITPNC1 facilitates the production of ROS while application of the ROS scavenger, N-acetyl-L-cysteine (NAC), could reverse this effect. CONCLUSIONS: PITPNC1 fuels radioresistance of rectal cancer via the inhibition of ROS generation.

Functional magnetic resonance imaging-based assessment of terlipressin vs. octreotide on renal function in cirrhotic patients with acute variceal bleeding (CHESS1903): study protocol of a multicenter randomized controlled trial.

BACKGROUND: Acute variceal bleeding is one of the critical complications in patients with liver cirrhosis. Severe renal vasoconstriction in consequence of low peripheral vascular resistance triggers the reduction of glomerular filtration rate (GFR), and thus induces acute kidney injury (AKI)/hepato-renal syndrome (HRS). Terlipressin and octreotide have been used in the management of cirrhotic patients with variceal bleeding. Also, terlipressin has been recommended as the international first-line pharmacological therapy for the treatment of HRS. In addition, the use of renal functional magnetic resonance imaging (fMRI) has become increasingly prevalent in research and clinical applications. However, the renal function-protective effect of terlipressin and octreotide and the value of fMRI in monitoring renal function remains unclear in patients with cirrhosis undergoing acute variceal bleeding. METHODS: This is a multicenter, randomized controlled trial (RCT). Participants will be 1:1 assigned randomly into either terlipressin or octreotide groups. Sixty participants with clinically and/or pathologically diagnosed cirrhosis and active gastroesophageal variceal bleeding (GVB) will be recruited in several sites in China. Participants will receive either the treatment of terlipressin or octreotide after assigned into each group. The primary end point for the trial is the renal function. The secondary end points are (I) renal perfusion; (II) renal blood oxygenation; (III) failure to control bleeding; (IV) intra-hospital rebleeding; (V) intra-hospital mortality; (VI) adverse events (AE); (VII) overall survival. Statistical analysis including multivariate Cox regression, Kaplan-Meier analysis with log-rank test, etc. will be conducted. DISCUSSION: The study will provide new insight into the protection of renal function in the process of the treatment of variceal bleeding in patients with cirrhosis. TRIAL REGISTRATION NUMBER: NCT04028323.

Engineering macrophages to phagocytose cancer cells by blocking the CD47/SIRPɑ axis.

The use of immunotherapy has achieved great advances in the treatment of cancer. Macrophages play a pivotal role in the immune defense system, serving both as phagocytes (removal of pathogens and cancer cells) and as antigen-presenting cells (activation of T cells). However, research regarding tumor immunotherapy is mainly focused on the adaptive immune system. The usefulness of innate immune cells (eg, macrophages) in the treatment of cancer has not been extensively investigated. Recent advances in synthetic biology and the increasing understanding of the cluster of differentiation 47/signal regulatory protein alpha (CD47/SIRPɑ) axis may provide new opportunities for the clinical application of engineered macrophages. The CD47/SIRPɑ axis is a major known pathway, repressing phagocytosis and activation of macrophages. In this article, we summarize the currently available evidence regarding the CD47/SIRPɑ axis, and immunotherapies based on blockage. In addition, we propose cell therapy strategies based on macrophage engineering.

Gastric cancer cells escape metabolic stress via the DLC3/MACC1 axis.

Metabolic stress usually occurs in rapidly growing gastric cancer (GC) when the energy demand exceeds the supply. Interestingly, cancer cells can somehow escape this stress. Some small Rho GTPases regulating cell migration can be activated by metabolic stress. DLC3 is a RhoA-specific GTPase-activating protein of unclear function in cancer. We hypothesized that it participated in metabolic stress escape. Methods: Metabolic stress in GC cells was induced by glucose deprivation, and DLC3 expression was detected. Based on the prognostic value, cell viability, motility and glycolysis were detected in DLC3 differently expressed GC cells in vitro and in vivo. DLC3 downstream targets were screened and verified. Chemotactic ability was evaluated to study DLC3 and its downstream signaling on metabolic stress escape. In addition, therapeutic strategies targeting DLC3 were explored. Results: DLC3 expression was lowered by metabolic stress in GC cells. DLC3 downregulation indicated poor cancer prognosis, and silencing DLC3 promoted GC cell proliferation and invasion. MACC1, an oncogene promoting GC growth and metastasis, was proved to be the downstream target of DLC3. Low DLC3 expression and high MACC1 expression indicated high recurrence rate after GC resection. DLC3 transcriptionally inhibited MACC1 expression via RhoA/JNK/AP-1 signaling, and subsequently suppressed GC cell glycolysis and survival under metabolic stress. The DLC3/MACC1 axis modulated the chemotaxis of GC cells from energy deficient area to glucose abundant area. Finally, lovastatin was found to be a promising therapeutic drug targeting the DLC3/MACC1 axis. Conclusions: The DLC3/MACC1 axis modulates GC glycolysis and chemotaxis to escape glucose deprivation. Lovastatin may inhibit GC by targeting the DLC3/MACC1 axis.

ATXN2L upregulated by epidermal growth factor promotes gastric cancer cell invasiveness and oxaliplatin resistance.

For gastric cancer (GC) control, metastasis and chemoresistance are the major challenges, accompanied with various stresses. Ataxin-2-like (ATXN2L) was discovered as a novel regulator of stress granules, yet its function in cancers remained unknown. Hence, we wanted to explore the functions of ATXN2L to see whether it participates in stress-related cancer malignant activities. Clinical follow-up was performed to see the impact of ATXN2L on GC patient survival. As a result, ATXN2L expression was upregulated in GC tissue and indicated adverse prognosis for overall survival and recurrence. In GC cells, ATXN2L expression was knocked down and functional experiments were performed. ATXN2L promoted GC cell migration and invasion via epithelial to mesenchymal transition, yet no influence on proliferation was detected by ATXN2L interference. When adding the chemotherapeutic agent oxaliplatin to induce stress, silencing ATXN2L sensitized GC cells to oxaliplatin. Interestingly, oxaliplatin was found to in turn promote ATXN2L expression and stress granule assembly. Then, two acquired oxaliplatin-resistant strains were generated by long-term oxaliplatin induction. The oxaliplatin-resistant strains presented with elevated ATXN2L levels, while silencing ATXN2L in the strains reversed the oxaliplatin resistance by increasing reactive oxygen species production and apoptosis. These results suggested that ATXN2L was responsible for not only intrinsic but also acquired oxaliplatin chemoresistance. Finally, ATXN2L-related signaling was screened using bioinformatic methods, and epidermal growth factor (EGF) was verified to promote ATXN2L expression via PI3K/Akt signaling activation. Blocking EGFR/ATXN2L signaling reversed GC cell oxaliplatin resistance and inhibited migration. In conclusion, ATXN2L promotes cell invasiveness and oxaliplatin resistance and can be upregulated by EGF via PI3K/Akt signaling. ATXN2L may be an indicator and therapeutic target in GC, especially for oxaliplatin-based chemotherapy.