臨床検体に対する集約的シングルセル解析と新規エピゲノム創薬

抄録

Epigenomes allow the rectification of disordered cancer gene expressions. This is the first study to illustrate patients’ molecular and cellular dynamics in response to an inhibitor designed for histone methyltransferase. We recently found the potency and mechanisms of action and resistance of an EZH1/2 dual inhibitor valemetostat in the clinical trials of patients with adult T-cell leukemia/lymphoma (ATL). Valemetostat administration reduced the tumor size and demonstrated durable clinical benefits. Integration of the intensive multilayered single-cell omics platform and clinical resources revealed that valemetostat abolished histone H3K27me3-mediated highly condensed chromatin and neutralized multiple gene loci, including tumor suppressor genes. Eliminating H3K27me3 led to reprogramming the cancer epigenome, thereby exerting a sustained benefit on tumors. Furthermore, both treatment-naive and treatment-adapted patients displayed the characteristic condensed chromatin structures, consistently suggesting that chromatin compaction is indispensable for tumor maintenance and growth. We hope that targeting the new concept “chromatin homeostasis” can provide a new avenue of vast opportunities for durable cancer treatment.