Indotecan (Lmp400), Imidotecan (Lmp776) And Lmp744: A New Class Of Non-Camptothecin Top1 Inhibitors Selective For Homologous Recombination Deficient (Hrd) Cells

To relax DNA supercoiling during transcription and replication, topoisomerase I (Top1) induces transient DNA cleavage complexes, which are trapped by anticancer drugs, leading to DNA double-strand breaks (DSB) that need to be repaired by homologous recombination (HR). BRCA1, BRCA2 and PALB2, which are key components for HR, lead to “synthetic lethality” with PARP inhibitors. Topotecan and irinotecan (camptothecin derivatives) are the only FDA-approved Top1 inhibitors. In spite of their wide usage they are plagued by their chemical instability, being drug efflux substrates, having short half-life, and dose-limiting bone marrow and gastro intestinal toxicity. It is now possible to overcome those limitations with the non-camptothecin indenoisoquinolines (LMP400, LMP776 and LMP744), which are in clinical trials. To rationally select patients for phase 2 clinical trials based on cancer-specific genomic alterations, we have determined whether the LMPs present a “synthetic lethality” toward BRCA1, BRCA2 or PALB2 deficiency, and whether this selectivity could be enhanced by combining them with the recently approved PARP inhibitor, olaparib.Using isogenic DT40 cell lines, with BRCA1, BRCA2 or PALB2 deficiencies, we assessed the role of HR in the cellular responses to the LMPs. Survival and cell cycle modifications were tested after treatment with the LMPs as single agents, as well as in combination with olaparib. We found that BRCA1-, BRCA2- and PALB2-deficient cells are 3 to 5 times hypersensitive to the LMPs (IC50’s for LMP400 and LMP744= 10 nM for HR-deficient cells vs. 45 nM for WT cells, and IC50 for LMP776 around 5 nM vs. 18 nM for WT cells). Cell cycle analyses confirmed the death of these HR-deficient cells. Moreover, combination treatments showed a significant synergy between each of the three LMPs and olaparib (Combination index Citation Format: Laetitia Marzi, Keli Agama, Zoe Weaver Ohler, Ludmila Szabova, Shyam Sharan, Junko Murai, Muthana Al Abo, Yves Pommier. Indotecan (LMP400), imidotecan (LMP776) and LMP744: A new class of non-camptothecin Top1 inhibitors selective for homologous recombination deficient (HRD) cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2794. doi:10.1158/1538-7445.AM2017-2794