Abstract P023: Achieving synergism in combination chemotherapy for gastric cancer treatment

Abstract

Abstract Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of deaths from cancer. Although the combination of conventional chemotherapeutics with molecular targeted agents targeting tumor-specific biomarkers has increased the treatment efficacy in certain types of cancer such as breast cancer, similar success could not be achieved in GC treatment. Therefore, there is an urgent need for combination protocols that can increase the therapeutic success in GC therapy. Synergism is the most important requirement for the success of drug combinations in cancer therapy. Besides the choice of anti-cancer agents included in combination protocols, the order of application and the time interval between drug applications, are important determinants of synergism. In this study, we aim to test whether sequential application of conventional chemotherapeutic-molecular targeted agent pairs can transform antagonistic response into synergistic response in GC. To achieve the goals of this study, we have screened dual combinations of five different chemotherapeutics from anthracyclins, platinium derivatives, taxanes, fluoropyrimidines and topoisomerase inhibitors, and three different molecular-targeted agents targeting EGFR, mTOR or c-Met in four different GC cell models to identify synergistic and antagonistic drug pairs. The most antagonistic drug pairs are selected to test whether sequential application schedules can transform antagonism into synergism for these drug pairs. Drug pairs that display strongest synergism in concomitant applications are also further analyzed in detail to investigate their potential in GC treatment. The degree of synergism is measured with Chou-Talalay Method, and apoptosis, autophagy and cell cycle responses were investigated to identify possible molecular mechanisms of synergism. Our data shows that sequential application schedules can transform antagonism into synergism. We believe that the treatment schedules that will be defined in this study can increase the success of chemotherapeutic-molecular targeted agent combinations in GC. Citation Format: Ozen Leylek, Gulnihal Ozcan. Achieving synergism in combination chemotherapy for gastric cancer treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P023.