To relax DNA supercoiling, topoisomerase I (TOP1) induces DNA cleavage complexes (TOP1cc). These TOP1cc can be trapped by camptothecin, leading to replication-induced DNA double-strand breaks (DSB). Widely used, camptothecin derivatives are plagued by limitations. It is now possible to overcome these limitations with the non-camptothecin indenoisoquinolines currently in clinical trials (the LMPs: LMP400, LMP776, and LMP744). Homologous recombination (HR) and its key components BRCA1, BRCA2, and PALB2 are needed to repair DSB induced by TOP1 inhibitors. It has been shown that BRCA1 is a determinant of response to camptothecins in addition to olaparib. Also, Schlafen11 (SLFN11) expression has been demonstrated to be a highly penetrant determinant of response to camptothecin derivatives. To rationally select patients for phase 2 clinical trials based on cancer-specific genomic alterations, we have determined whether HR components deficiency or SLFN11 expression are determinants of LMPs response. Using isogenic cell lines, we assessed the survival and cell cycle modifications after treatment with the LMPs. We found that SLFN11-negative cells are 10 times hypersensitive to LMPs compared to WT cells. Also, BRCA1-, BRCA2-, and PALB2-deficient cells are 3 to 5 times hypersensitive to the LMPs. Adding olaparib led to a greater cell death, especially in HR-deficient cells. Our results show that the indenoisoquinolines are active at nanomolar concentrations and that HR deficiency and SLFN11 expression are strong drug response determinants. They also demonstrate that the LMPs synergize with olaparib. These findings provide a rationale for personalized treatment and further clinical trials with the indenoisoquinolines in HR-deficient cancers.

Citation Format: Laetitia Marzi, Yves G. Pommier. New class of TOP1 inhibitors selective for HR deficiencies and SLFN11 expression [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B189.