The MYC Paralog-PARP1 Axis as a Potential Therapeutic Target in MYC Paralog-Activated Small Cell Lung Cancer

Frontiers in Oncology

Jun Huang¹  Ao Xu²  Guozhen Cao³  Liying Ma³  Xiaolin Wang³  Xing Bian³  Wenchu Lin⁴  Jinhua Han⁶  Qiuyan Zhang⁷ 

[1] Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China;Department of Pathology, Anhui Provincial Hospital, Hefei, China;High Magnetic Field Laboratory of Anhui Province, Hefei, China;High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, China;Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, China;;MOE Key Laboratory for Biosystems Homeostasis &The CAS Key Laboratory of Innate Immunity and Chronic Disease, Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, China;The First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China;University of Science and Technology of China, Hefei, China;

关键词: small cell lung cancer;    MYC paralog;    PARP1;    BET;    DNA damage response;   

DOI  :  10.3389/fonc.2020.565820

来源: DOAJ

【 摘 要 】

Poly (ADP-ribose) polymerase 1 (PARP1) is highly expressed in small cell lung cancer (SCLC) and has emerged as an attractive target for treatment of SCLC. However, the clinical significance of PARP1 expression in SCLC remains elusive. In this study, we showed that high PARP1 expression was associated with better overall survival (OS), and was positively correlated with the expression of MYC paralogs in patients with SCLC. We demonstrated that PARP1 was transcriptionally regulated by MYC paralogs. Integrative analysis of multiple RNA-seq data sets indicated that DNA damage response (DDR) genes involved in the replication stress response (RSR) and homologous recombination (HR) repair pathways were highly enriched in MYC paralog-addicted SCLC cell models and in human SCLC specimens. Targeting the MYC paralog-PARP1 axis with concomitant BET and PARP inhibition resulted in synergistic effects in MYC paralog-activated SCLC. Our study identified a critical PARP1 regulatory pathway, and provided evidence for a rational combination treatment strategy for MYC paralog-activated SCLC.

【 授权许可】

Unknown