Abstract 2794: Indotecan (LMP400), imidotecan (LMP776) and LMP744: A new class of non-camptothecin Top1 inhibitors selective for homologous recombination deficient (HRD) cells
Authors: Marzi Laetitia , Agama Keli , Ohler Zoe Weaver , Szabova Ludmila , Sharan Shyam , Murai Junko , Abo Muthana Al , Pommier Yves 
Published: July 2017

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&lt;0.7). The HR-deficient cells being markedly more sensitive than WT cells (taken as surrogate for normal tissues) to both treatments, led to a better response to the combination in those cells.Our results show that the LMPs are active at nanomolar concentrations, selectively in HR-deficient cells, indicative of a “synthetic lethality” of the indenoisoquinolines (LMPs) with HRD genotypes. They also demonstrate that the LMPs synergize with olaparib. These findings provide a rationale for personalized treatment and Phase 2 clinical trials with the indenoisoquinolines in combination with PARP inhibitors in HR-deficient cancers.

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