CellMinerCDB snapshots (http://discover.nci.nih.gov/cellminercdb) demonstrating the correlations between the activity of the three clinical indenoisoquinolines and SLFN11 expression in the NCI-60 (A-C) and in the GDSC (MGH-Sanger) panels of non-isogenic cancer cell lines. Each dot represents a cell line [59 cell lines are shown for the NCI-60 (A-C) and 712 cell lines are included in the GDSC plot (D). LMP compounds are listed by their NSC numbers in the NCI-60 panels A-C (LMP400 = NSC724998; LMP744 = NSC706744 and LMP776 = NSC725776). LMP744 a is also referred as MJ-III-65 in the GDSC (MGH-Sanger) database.
ARTICLE ABSTRACTIrinotecan and topotecan are used to treat a variety of different cancers. However, they have limitations, including chemical instability and severe side effects. To overcome these limitations, we developed the clinical indenoisoquinolines: LMP400 (indotecan), LMP776 (indimitecan), and LMP744. The purpose of the study is to build the molecular rationale for phase II clinical trials.
CellMinerCDB (http://discover.nci.nih.gov/cellminercdb) was used to mine the cancer cell lines genomic databases. The causality of Schlafen11 (SLFN11) was validated in isogenic cell lines. Because topoisomerase I (TOP1)-mediated replication DNA damage is repaired by homologous recombination (HR), we tested the “synthetic lethality” of HR-deficient (HRD) cells. Survival and cell-cycle alterations were performed after drug treatments in isogenic DT40, DLD1, and OVCAR cell lines with BRCA1, BRCA2, or PALB2 deficiencies and in organoids cultured from prostate cancer patient-derived xenografts with BRCA2 loss. We also used an ovarian orthotopic allograft model with BRCA1 loss to validate the efficacy of LMP400 and olaparib combination.
CellMinerCDB reveals that SLFN11, which kills cells undergoing replicative stress, is a dominant drug determinant to the clinical indenoisoquinolines. In addition, BRCA1-, BRCA2-, and PALB2-deficient cells were hypersensitive to the indenoisoquinolines. All 3 clinical indenoisoquinolines were also synergistic with olaparib, especially in the HRD cells. The synergy between LMP400 and olaparib was confirmed in the orthotopic allograft model harboring BRCA1 loss.
Our results provide a rationale for molecularly designed clinical trials with the indenoisoquinolines as single agents and in combination with PARP inhibitors in HRD cancers expressing SLFN11.