Abstract 5367: DNA-PKcs inhibitors impair OCT4-mediated MYC transcriptional activation in small cell lung cancer

Abstract

Abstract Small cell lung cancer (SCLC) is a disease found almost exclusively in smokers and is a highly aggressive cancer with incredibly poor outcomes. Initially, most patients diagnosed with SCLC respond to platinum + etoposide (PE)-based therapy, but relapse occurs in nearly all patients and is fatal. SCLC is a cancer with a heavy mutational burden, and loss-of-function mutations of the tumor suppressor genes RB1 and TP53 are nearly ubiquitous in SCLC tumors. Amplification and overexpression of the MYC of oncogene occurs in a subset of SCLC tumors that are associated with tumor progression, treatment resistance, and poor outcomes, therefore we pursued the inhibition of the MYC activation. The purpose of this study is to inhibit a novel pathway of MYC transcriptional activation via DNA-PKcs-mediated phosphorylation of OCT4 at its Ser93 residue in SCLC, a MYC transcriptional activation pathway that we discovered. We identified OCT4 being a transcription factor that primarily induce MYC activation. Subsequently, Serine 93 residue of OCT4, a new OCT-4 binding site, was phosphorylated by DNA-PKcs that was a critical step for OCT4-induced MYC activation. In a panel of 19 small cell lung cancer, DNA-PKcs, phosphorylation of OCT4 at Ser93, and c-MYC were positively correlated. We confirmed the binding of DNA-PKcs to OCT4 and identified novel OCT4-binding sites in the MYC promoter/enhancer region that regulated MYC expression via phosphorylation by DNA-PKcs, and DNA-PKcs or OCT4 knockdown decreased c-MYC expression. DNA-PKcs inhibitors also reduced phosphorylation of OCT4 at Ser93 leading to decreases in c-MYC and showed cytotoxic effects via inducing apoptosis by DNA-PKcs inhibitors. DNA-PKcs inhibitors augments antitumor activity of Bcl-2 inhibitors cell lines and xenograft models of small cell lung cancer. In conclusion, report here that DNA-PKcs-mediated phosphorylation of OCT4 at Ser93 is a novel mechanism for activating the MYC oncogene in SCLC, and that DNA-PKcs is a viable target to decrease c-MYC expression in these highly aggressive tumors. Citation Format: Inhyoung Yang, Ismail Mohiuddin, Sung-Jen Wei, Martinez Gloria, Min H. Kang. DNA-PKcs inhibitors impair OCT4-mediated MYC transcriptional activation in small cell lung cancer [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 5367.