Abstract 4064: Synergistic activity of Lurbinectidin plus ONC201 in SCLC is associated with ATF4, CHOP and pChk1 induction

Abstract

Abstract Small cell lung cancer (SCLC) accounts for 15% of lung cancer and is responsive to chemotherapy but most patients relapse with drug-resistant disease and have very poor 5-year survival of less than 7%. One of the most notable advances in the last decade has been the approval of lurbinectedin for platinum resistant SCLC. Lurbinectedin is a small molecule inhibitor, targeting RNA polymerase II, and binding the minor grooves of DNA to induce double-strand breaks. The dismal SCLC survival rate underscores the need for a novel combination to increase patient survival outcomes. ONC201 is a pro-apoptotic TRAIL-inducing compound that activates the integrated stress response and appears to have efficacy in neuroendocrine tumors including paragangliomas. In our preclinical experiments, we explored the combination of ONC201 and lurbinectedin as a potentially effective treatment regimen for SCLC. Lurbinectedin has been shown to have effective cancer cell killing ability in multiple SCLC cell lines (H1048, H1105, H1882, H1417) at sub-nanomolar concentrations, while sparing healthy lung epithelial tissue cells (cell line HSAEC). We hypothesized that combining ONC201 and lurbinectedin will yield synergistic outcomes due to combining drugs that act by different potentially complementary mechanisms. We treated SCLC cell lines with ONC201 and lurbinectedin at increasing concentrations of the drugs. CellTiter Glo was used to perform cell viability assays, and combination index analysis (Combenefit software) revealed the most synergy between the agents occurred at the concentrations of 0.156 uM ONC201 and 0.047 nM lurbinectedin. We are expanding this combination’s efficacy in other SCLC lines and tumor types. Western blotting further examined these synergies and showed that PARP cleavage and expression of ATF4 and TRAIL death receptor DR5 were increased at higher concentrations of these agents. We further noted that combinatorial treatment with these agents induced marked upregulation of Phosphorylated Chk1 and CHOP at the highest treatment concentrations versus lower concentrations and control. These effects indicate effectiveness of the combinatorial treatment in causing DNA damage and instability, inducing double-stranded DNA breaks, as well as initiating the intrinsic apoptosis pathway through the integrated stress response, selectively in the malignant cells. Ongoing directions include testing similar concentrations of both ONC201 and lurbinectedin in additional SCLC cell lines, SCLC patient-derived organoids, and in vivo, as well as exploring immune correlates of the drug treatments. Keywords: SCLC; lurbinectedin; chemotherapy; imipridones; genomics Citation Format: Nicholas R. Liguori, Ashley Fss Uruchurtu, Young Lee, Leiqing Zhang, Abbas Abbas, Varun Prabhu, Lanlan Zhou, Christopher J. Azzoli, Wafik S. El-Deiry. Synergistic activity of Lurbinectidin plus ONC201 in SCLC is associated with ATF4, CHOP and pChk1 induction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4064.