Abstract 2575: EZH2 mediates resistance to cisplatin in small cell lung cancer through nucleotide excision repair

Small cell lung cancer (SCLC) is the most aggressive form of lung cancer, with a five-year survival rate of 7%. Cisplatin-based chemotherapy is the first line treatment for SCLC; however, many patients develop treatment resistance and experience tumor recurrence. Targeting proteins critical to the repair of cisplatin DNA crosslinks is a strategy for overcoming acquired cisplatin resistance in SCLC, but many proteins that mediate crosslink repair have yet to be identified. To address this issue, we performed a synthetic lethal siRNA screen in cisplatin resistant SCLC cells, and identified EZH2 as one of the strongest mediators of cisplatin resistance. EZH2 localizes to sites of DNA damage which are induced by UVA-crosslinking laser microirradiation and interacts in a complex with DDB1, and DDB2, members of the nucleotide excision repair (NER) pathway. Loss of EZH2 sensitizes SCLC cells to UV damage, and further, loss of EZH2 and DDB1 together are epistatic in the sensitization of SCLC to cisplatin, confirming a role for EZH2 in NER. Specifically, EZH2 promotes the stability of DDB2, which is responsible for the detection NER lesions. This occurs independently of EZH2’s methyltransferase activity on H3K27. Finally, we found EZH2 expression correlates with cisplatin resistance across SCLC cell lines. Together, this data suggests that EZH2 functions as a novel regulator of NER, and that EZH2 is a promising target for cisplatin resistant SCLC. Citation Format: Allyson E. Koyen. EZH2 mediates resistance to cisplatin in small cell lung cancer through nucleotide excision repair [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2575.