BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
Menée à l'aide de 40 xénogreffes dérivées de tumeurs de patientes atteintes d'un cancer du sein triple négatif, cette étude met en évidence une association entre le profil "BRCAness" de la tumeur (défaut de la réparation de l’ADN homologue liée ou non à une mutation du gène BRCA), le niveau d'expression de SLFN11, la perte de l'expression de RB1 et la réponse thérapeutique aux inhibiteurs de topoisomérase de type I
Topoisomerase (TOP) inhibitors are chemotherapeutic drugs that cause DNA double-strand breaks during DNA replication. These can be repaired by homologous recombination, but some tumors, such as triple-negative breast cancer, have defects in proteins needed for this type of repair. By examining 40 patient-derived xenograft models of triple-negative breast cancer, Coussy et al. identified three key features associated with response to topoisomerase inhibitors in these tumors. The authors characterized the extent of DNA damage in cancer cells in the presence or absence of their proposed markers and tested a potential intervention for increasing drug sensitivity in tumors missing one of the three target features.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.
Science Translational Medicine , résumé, 2019