소세포폐암에서 CDK7 표적억제제를 활용한 항암 효과 규명 연구

Abstract

In contrast to non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) has not been significant progress in the development of therapies for the disease for decades. Although various targeted agents including immunotherapy are recently being developed into a drug for testing in clinical trials, the development of new therapeutic agents are needed for SCLC. We developed a potent inhibitor of cyclin-dependent kinase 7 (CDK7), designated YPN-005, and searched anti-cancer effects in SCLC cells, cisplatin or etoposide-resistant cells and organoids derived from SCLC patients. In a panel of kinases assay, YPN-005 was highly selective for CDK7 and showed antiproliferative effects in SCLC as well as cells with acquired resistance to conventional anti-cancer drugs. Consistent with other CDK7 inhibitor, YPN-005 treatment significantly decreased the phosphorylation of the carboxyl-terminal domain of RNA polymerase II. In consistent with in vitro results, YPN-005 treatment showed a significant inhibition of tumor growth though the suppression of RNA polymerase II phosphorylation. Lastly, we found that YPN-005 showed potent anticancer effects in organoids derived from SCLC patients compared to other CDK7 inhibitor, THZ1. Therapeutic targeting of CDK7 in SCLC might be suitable for clinical investigation, and YPN-005 may be a promising therapeutic option for primary SCLC and SCLC with acquired resistance to conventional therapy.