Abstract
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.
Highlights
Small cell lung cancer is a high-grade neuroendocrine carcinoma that accounts for over 250,000 annual cases worldwide [1, 2]
These findings suggest that Poly (ADP-ribose) polymerase 1 (PARP1) expression may be a novel prognostic marker of small cell lung cancer (SCLC), and MYC paralog expression positively correlates with PARP1 expression
We showed that PARP1, a promising therapeutic target in SCLC, might be a potential prognostic marker
Summary
Small cell lung cancer is a high-grade neuroendocrine carcinoma that accounts for over 250,000 annual cases worldwide [1, 2]. In the past few decades, platinum-based chemotherapy with or without radiation has been the standard of care for the treatment of patients with SCLC [3]. The initial response rate to standard treatment is high, patients with SCLC often experience relapse within one year, and the 5-year survival rate is only 7 percent [4]. Treatment with PARP inhibitors (PARPi) alone or in combination with chemotherapy has been shown to induce beneficial therapeutic effects against SCLC in preclinical and clinical studies [7,8,9,10,11].
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