10199-SPDR-2 PERSONALIZED SYNTHETIC LETHALITY INDUCED BY TARGETING ATR-CHK1 IN MEDULLOBLASTOMAS IDENTIFIED BY IMPLEMENTATION OF SLFN11 IMMUNOHISTOCHEMISTRY

Abstract

Abstract Survival in medulloblastoma varies widely between molecular subgroups, and risk-adapted treatment stratification is necessary. Schlafen family member 11 (SLFN11) defines sensitivity to DNA-damaging therapies in a variety of cancers and may be useful in stratifying medulloblastomas. We previously showed that SLFN11 immunohistochemistry identifies poor-prognosis groups that lack expression; however, the additional treatment for these groups has not been fully elucidated. The serine/threonine kinase ATR (ataxia telangiectasia and Rad3-related) binds to single-stranded DNA upon DNA damage competing with SLFN11 and leads to cell cycle arrest and DNA repair process via Chk1 phosphorylation. Although therapeutic effects of ATR/Chk1 inhibitors on SLFN11-deficient cell lines have been reported in other carcinomas, little is known on brain tumors. In the present study, we investigated the effect of ATR/Chk1 inhibition on SLFN11-negative medulloblastomas. ATR knockdown was introduced to the medulloblastoma cell line DAOY and the isogenic SLFN11-knockout line DYB9, and only DYB9 showed increased sensitivity to cisplatin (Prestoblue assay, p < 0.05, t-test). The ATR inhibitor ceralasertib and the Chk1 inhibitor prexasertib also increased cisplatin and camptothecin sensitivity in DYB9 and SLFN11-low Group 3 medulloblastoma D425. Furthermore, combination therapy with cisplatin and prexasertib inhibited the growth of D425 cerebellar tumors (Akaluc IVIS imaging, p < 0.05, t-test) and prolonged survival of the mice (p < 0.05, Log-rank). Combination therapy with irradiation is currently under investigation. Evaluation of SLFN11 expression in medulloblastoma may lead to new treatment strategies, such as reduced radiation dose for the SLFN11-high groups and the combination therapy with ATR/Chk1 inhibitors for the low-expressing groups.