Abstract
Small cell lung cancer (SCLC) is an aggressive type of lung cancer with high mortality that is caused by frequent relapses and acquired resistance. Despite that several target-based approaches with potential therapeutic impact on SCLC have been identified, numerous targeted drugs have not been successful in providing improvements in cancer patients when used as single agents. A combination of targeted therapies could be a strategy to induce maximum lethal effects on cancer cells. As a starting point in the development of new drug combination strategies for the treatment of SCLC, we performed a mid-throughput screening assay by treating a panel of SCLC cell lines with BETi or AKi in combination with PARPi or EZH2i. We observed drug synergy between I-BET762 and Talazoparib, BETi and PARPi, respectively, in SCLC cells. Combinatorial efficacy was observed in MYCs-amplified and MYCs-wt SCLC cells over SCLC cells with impaired MYC signaling pathway or non-tumor cells. We indicate that drug synergy between I-BET762 and Talazoparib is associated with the attenuation HR-DSBR process and the downregulation of various players of DNA damage response by BET inhibition, such as CHEK2, PTEN, NBN, and FANCC. Our results provide a rationale for the development of new combinatorial strategies for the treatment of SCLC.
Highlights
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer [1,2]
A battery of 10 SCLC cell lines were grown as 3D tumor spheroids and treated with eight small molecule inhibitors, two for each target (Tables 1 and 2), in order to assess the efficacy of Bromodomain and Extra-Terminal domain (BET) or Aurora Kinase inhibition in combination with Enhancer of Zeste Homolog 2 (EZH2) or Poly-(ADP)-ribose polymerase-1 (PARP-1) inhibition on SCLC cells [35,36,37,38,39]
A combination of I-BET762 and Olaparib, the remaining tested PARP inhibitor, showed higher cytotoxicity in H2171, H446, Lu135, and H345 SCLC cells when compared to single agents, confirming the additive effect by I-BET762 with PARP inhibition (Figures S2 and S3)
Summary
Small cell lung cancer (SCLC) is the most aggressive type of lung cancer [1,2]. Genome-wide analyses in SCLC specimens confirmed, in ~15% of cases, gene amplification of one of the members of the MYC gene family, MYC, MYCL, or MYCN (hereafter MYCs) [3,4]. We previously reported that cell cycle arrest and apoptosis were consequences of MYC inhibition in SCLC cells, which indicated that MYCs could be targets for therapy in a subset of SCLC patients [5]. A pharmacological approach for inhibiting MYCs activity is represented by Bromodomain and Extra-Terminal domain (BET) inhibitors [6]. The suppression of MYCs activities by BET inhibitors (BETi) was reported in various types of tumors, including SCLC [10,11,12]
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