公開日 2025.11.18
（第284回 遺伝子機能解析部門セミナー）
演題 Probing genome-wide gene network to elucidate mode of action of chemotherapeutic drug combination
Ee-Sin Chen 氏（シンガポール国⽴⼤学⽣化学部）
Contemporary medical treatments such as anti-cancer chemotherapy entails the use of combination of multiple drugs. This approach is based on the synthetic lethality principle that involves concurrently targeting synergistically acting physiological pathways to bring about cumulative efficacy over that achievable by single drugs. These pathways are rather discrete, constituted by proteins expressed from genes in the genome that are widely depicted in the text-book knowledge taught to undergraduate students. However, in actual scenario, genes transcribed from eukaryotic genomes are organized into a much more expanded complex network, much of the time between unsuspected genes present in seemingly unrelated pathways. Such complexity may underlie bypass mechanisms that confer development of resistance to the prescribed pharmacological drugs. Several years ago, our lab used fission yeast as a model to attempt to visualize the gene network that underlies resistance against the chemotherapeutic drug doxorubicin, a topoisomerase II inhibitor. From the study, we observed that genes encoding previously unsuspected factors such as coenzyme Q10 biosynthesis pathway and centromeric determinant CENP-A histone H3 variant were functionally interacting with topoisomerase II to confer tolerance towards doxorubicin. Subsequent analysis dawned on us that the “doxorubicin-resistance” network is actually a more ʻgenericʼ one that coordinates responsiveness toward multiple environmental stressors including drugs of unrelated mode of action and inorganic factors such as cations. Further, we were surprised to find out such gene network appeared to also be conserved, thus permitting us to employ fission yeast model to predict new drug combination efficacious in human cancers, importantly , before understanding the actual mechanism of action. I will discuss one such combination between doxorubicin, SAHA and cisplatin, later found to act via disrupting the target of rapamycin (TOR)-regulated protein synthesis of DNA damage response factors to result in persistent presence of DNA damage for apoptosis induction in human gastric cancer cells.