Abstract A05: Derivation of chemotherapeutic combination against gastric cancer cells via synthetic lethal targeting of conserved drug-resistance network in fission yeast surrogate
Authors: Chen Eesin-. , Seah Kwishan-. , Nguyen Thuytrang-. 
Published: December 2017

Cancer is a global health problem and there is a critical need for new advancements in its management and treatment if we are to meet the projected increase in new cases. One important challenge facing clinicians is how to determine the most appropriate treatment strategy for patients. Thus far, chemotherapy has remained the mainstay for cancer management. Contemporary chemotherapeutic treatments incorporate the use of typically three to four agents in combination. The determination of the most suitable drug combination profoundly affects chemotherapeutic success. However, selecting the most appropriate drugs for such therapy is not necessarily a straightforward task. Here, we describe a targeted approach that can facilitate the reliable selection of chemotherapeutic drug combinations through the interrogation of drug-resistance gene networks. Our approach employed the single-cell eukaryote fission yeast (Schizosaccharomyces pombe) as a model of proliferating cells using a synthetic lethality workflow. Using a group of genes that we have uncovered to confer responsiveness towards the topoisomerase II inhibitor doxorubicin, a widely applied therapeutic agent in a wide range of cancers. We assessed the genetic overlap of the doxorubicin responsive network with that of several other chemotherapeutic agents harboring varied mechanisms of action. From these effort, we have determined a synergistic combination between three chemotherapeutic agents that include the intrastrand crosslinking agent cisplatin, histone deacetylase inhibitor suberoylanilide acid (SAHA) with doxorubicin. Interestingly, our results revealed that SAHA and doxorubicin affect the integrity of the chromatin at the centromeric core domain to undermine chromosome segregation fidelity. On the other hand, we and others have reported that doxorubicin and cisplatin result in DNA damage in fission yeast cells and dependent upon homologous recombination machinery for proper repair. These results suggest that the mechanism of action of the combined effect of these drugs is mediated via induction of genomic instability following imprecise mitotic chromosome segregation and the damaging of DNA. We further showed that the drug combination can inflict apoptotic cell death in human gastric adenocarcinoma cells, which exhibited cleavage of caspases and the poly ADP ribose polymerase upon drug treatment. The cells also displayed changes in epigenetic modifications that included the upregulation of phosphorylation of histone H2AX, which is a marker for DNA damage, as well as global alteration in histone acetylation level, latter mainly due to the treatment with SAHA. Concomitantly, activities of several cell signalling kinases were altered in the gastric adenocarcinoma cells upon drug treatment indicative of the pathway specificity that relayed the damage signals in response to the drugs. Taken together our findings point to the usefulness of fission yeast as a model in revealing in screening for successful chemotherapeutic drug combinations for human cells via differential targeting of a conserved gene interaction network.

Citation Format: Eesin-. Chen, Kwishan-. Seah, Thuytrang-. Nguyen. Derivation of chemotherapeutic combination against gastric cancer cells via synthetic lethal targeting of conserved drug-resistance network in fission yeast surrogate [abstract]. In: Proceedings of the AACR Precision Medicine Series: Opportunities and Challenges of Exploiting Synthetic Lethality in Cancer; Jan 4-7, 2017; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2017;16(10 Suppl):Abstract nr A05.