The novel SMYD3 inhibitor EM127 impairs DNA repair response to chemotherapy-induced DNA damage and reverses cancer chemoresistance.

BACKGROUND: SMYD3 has been found implicated in cancer progression. Its overexpression correlates with cancer growth and invasion, especially in gastrointestinal tumors. SMYD3 transactivates multiple oncogenic mechanisms, favoring cancer development. Moreover, it was recently shown that SMYD3 is required for DNA restoration by promoting homologous recombination (HR) repair. METHODS: In cellulo and in vivo models were employed to investigate the role of SMYD3 in cancer chemoresistance. Analyses of SMYD3-KO cells, drug-resistant cancer cell lines, patients' residual gastric or rectal tumors that were resected after neoadjuvant therapy and mice models were performed. In addition, the novel SMYD3 covalent inhibitor EM127 was used to evaluate the impact of manipulating SMYD3 activity on the sensitization of cancer cell lines, tumorspheres and cancer murine models to chemotherapeutics (CHTs). RESULTS: Here we report that SMYD3 mediates cancer cell sensitivity to CHTs. Indeed, cancer cells lacking SMYD3 functions showed increased responsiveness to CHTs, while restoring its expression promoted chemoresistance. Specifically, SMYD3 is essential for the repair of CHT-induced double-strand breaks as it methylates the upstream sensor ATM and allows HR cascade propagation through CHK2 and p53 phosphorylation, thereby promoting cancer cell survival. SMYD3 inhibition with the novel compound EM127 showed a synergistic effect with CHTs in colorectal, gastric, and breast cancer cells, tumorspheres, and preclinical colorectal cancer models. CONCLUSIONS: Overall, our results show that targeting SMYD3 may be an effective therapeutic strategy to overcome chemoresistance.

Efficacy of Intragastric Balloon versus Liraglutide as Bridge to Surgery in Super-Obese Patients.

INTRODUCTION: Bariatric surgery is a safe and effective treatment for obesity, although in super-obese patients (BMI ≥50 kg/m2) it can become challenging for anatomical and anesthesiologic issues. Several bridging therapies have been proposed to increase preoperative weight loss and decrease perioperative morbidity and mortality. The aim of this study was to compare the efficacy and safety of different two-stage approaches in super-obese patients: laparoscopic sleeve gastrectomy (LSG) following preoperative liraglutide therapy versus LSG with preoperative intragastric balloon (IGB) during a 1-year follow-up. METHODS: Clinical records of 86 patients affected by super-obesity who underwent two-stage approach between January 2019 and January 2022 were retrospectively reviewed using a prospectively maintained database. Patients were separated into two groups: those managed with preoperative IGB and those with liraglutide 3.0 mg prior to LSG. Weight (kg), BMI (kg/m2), %EWL, and %EBWL were reported and compared between the two groups at the end of bridging therapy, at 6th month and 12th month postoperatively. Postoperative complications were recorded. RESULTS: Forty-four patients underwent IGB insertion prior to LSG, while 42 were treated with liraglutide. There were no statistical differences in baseline weight and BMI. At the end of preoperative treatment, the group treated with IGB reported a significant reduction in BMI (47.24 kg/m2 vs. 53.6 kg/m2; p < 0.391) compared to liraglutide group. There were no differences recorded between the two groups concerning postoperative complications. At 6 months, the liraglutide group had lower %EWL (15.8 vs. 29.84; p < 0.05) and %EBWL (27.8 vs. 55.6; p < 0.05) when compared to IGB group. At 12 months, the IGB preserved with higher %EWL (39.9 vs. 25; p < 0.05) and %EBWL (71.2 vs. 42; p < 0.05). CONCLUSION: A two-stage therapeutic approach with IGB prior to LSG in super-obese patients could be considered an attractive alternative to liraglutide as bridging therapy before bariatric surgery.