Objective: Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine malignancy. Post-platinum-based chemotherapy, rapid relapse of chemoresistant tumor is commonly seen. Unidentifiable causative mutations and from reversible nature of acquired chemoresistance, involvement of epigenetic switch regulating SCLC progression is evident. Aim of this screen is to identify epigenetic modifiers that could sensitize SCLC cells to ionizing radiation (IR).

Methods: To recapitulate molecular diversity of patients, a range of SCLC cell lines (n=10) from classic or variant and ASCL1 or NeuroD1 sub-groups, driven by varying MYC family amplifications were picked. Short term viability experiment was setup in 3 groups: (a) Epigenetic monotherapy: cells were screened with 10 epigenetic modifiers (0 to 10 µM). (b) IR monotherapy: cells were irradiated from 0 to 8 gy. (c) Combination therapy: cells were treated with different doses of epigenetic probes and IR. Radiosensitization was measured as dose modifying factor at SF63 for each epigenetic modulator.

Results: (a) Epigenetic monotherapy: All 10 cell lines were responsive to GSK-J4 (KDMi, IC50 3.1-0.9 µM), SAHA (HDACi, IC50 2.9-0.79 µM) and JIB04 (Jumonji KDMi, IC50 74-2.4 nM). Other interesting epi-probe to which 9/10 cell lines responded was JQ1 (BET-BRDi, IC50 5.7 to 0.15 µM, except SBC-5). Compounds with lesser universal potency were MS023 (PRMTi), UNC0642 (G9a/GLPi) and UNC1999 (EZH2i). All cell lines were irresponsive to PFI3 (SMARCA2/4 BRDi), BAY598 (SMYD2 MTi) and OICR-9429 (WDR5i). (b) IR monotherapy: All 10 cell lines demonstrated different sensitivities to 4 days of IR. They’re ranked in descending order of radiosensitivity as H446, H82, SHP77, LX22, H889, H1092, H196, H69, SBC5, H526. (c) Epi-probes + IR combination therapy: Epi-probes ranked in descending order of number of cell lines they radiosensitized are JQ1, JIB-04, GSK-J4, SAHA, UNC0642, BAY598, MS023, UNC1999, OICR9429 and PFI3. Interestingly, drugs that demonstrated potency as a single agent did not necessarily radiosensitize the cell lines. On the contrary, certain epi-probes that were ineffective as monotherapy radiosensitized a few of the cell lines. H82 is a sensitive cell line which was radiosensitized by all epi-probes used.

Conclusions: This screen shows that treating cells with IR in conjunction with epigenetic modifiers may potentially improve therapeutic efficacy of radiotherapy in SCLC. Further validation is being done with long term colonogenic assays followed by in vivo studies for the potent radiosensitizing candidate drugs. It would be therapeutically relevant to correlate the probability of radiosensitization by an epi-probe with the molecular profile of the patients for more predictive targeted therapeutics.

Citation Format: Mansi K. Aparnathi, Lifang Song, Ratheesh Subramaniam, Richard Marcellus, Rima Al-awar, Benjamin H. Lok. A screen for epigenetic radiosensitizers in small cell lung cancer [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 3925.