BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers

Abstract

Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.

Effects of germline and somatic events in candidate BRCA-like genes on breast-tumor signatures

“…For example, in mice, inactivation of the Bard1 protein induces mammary tumors that are indistinguishable from tumors that result from Brca1 knock-out [100]. In triple-negative breast cancers, ATR inhibitors are highly efficient in patient-derived xenografts that have a BRCA1 mutation or that exhibit the BRCA-like phenocopy when combined with irinotecan, a clinically approved topoisomerase 1 inhibitor that causes double-stranded breaks [101].…”

Synthetic Lethal Activity of Benzophenanthridine Alkaloids From Zanthoxylum coco Against BRCA1-Deficient Cancer Cells

“…First, it was shown that AKT inhibition using the investigational drug MK-2206 suppresses the initiation and progression of BRCA1-associated mammary tumors (Baek et al, 2018). Second, a recent report indicates that BRCA deficiencies predict response to topoisomerase I inhibitors in 40 PDXs obtained from triple-negative breast cancers patients (Coussy et al, 2020).…”

New Perspectives for Resistance to PARP Inhibitors in Triple-Negative Breast Cancer

“…Schlafen 11 (SLFN11) is an indirect factor in replication stress by selectively activating ATPase of the chromatin opening domain to arrest replication fork progression. It selectively binds chromatin through RPA1 and MCM3, instead of phosphorylating ATR or inhibiting the initiation of DNA replication forks under replication stress (113). On the other hand, tumor cells are sensitized by SLFN11 to multiple DNA-targeting drugs, including platinum derivatives, PARPi, inhibitors of topoisomerases, and DNA synthesis inhibitors.…”