Biology subjects

Leo, E.

Publications and source records attributed to Leo, E..

3 recordsLinked to original sources

bioRxiv2025

Androgen receptor inhibition extends PARP inhibitor activity in prostate cancer models beyond BRCA mutations and defects in homologous recombination repair.

Recent phase 3 clinical trial readouts have shown benefit of the combination of poly(ADP-ribose) polymerase inhibitors (PARPi) with androgen receptor (AR) pathway inhibitors (ARPi) in metastatic, castration-resistant prostate cancer (mCRPC). While benefit was particularly evident in patients with tumours harbouring mutations in homologous recombination repair (HRR) genes, improved outcomes were also observed in patients with no such defined alterations in their cancers. Although there is literature linking AR activity with DNA repair pathways, the basis of the interaction between the AR and PARP is unclear. Here, we show that benefit of the combination of ARPi and PARPi in prostate cancer in vitro and in vivo models with no HRR mutations requires ARPi-responsive cells and a PARPi with PARP1-trapping activity, and does not involve an effect of PARPi treatment in modulating the transcriptional role of the AR. Combination benefit is driven by an increase in DNA damage in the form of DNA double-strand breaks and micronuclei formation, which is not due to a direct control of HRR gene transcription by the AR. In addition, we uncover a novel role of PARP1 in modulating AR recruitment to chromatin in the presence of DNA damage. These data shed new light on the interplay between PARP1 and the AR in dealing with genotoxic insults and provide a mechanism of action consistent with the observed clinical benefit of the combination of PARPi and ARPi in patients with prostate cancer. Statement of significanceCombination of androgen receptor pathway inhibitors and PARP inhibitors has shown efficacy in prostate cancer. We provide a mechanistic explanation through increased DNA damage accumulation observed in combination vs single-agent treatments.

cancer biology↗

bioRxiv2022

Drug-gene interaction screens coupled to tumour data analyses identify the most clinically-relevant cancer vulnerabilities driving sensitivity to PARP inhibition

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are currently indicated for the treatment of ovarian, breast, pancreatic and prostate cancers harbouring mutations in the tumour suppressor genes BRCA1 or BRCA2. In the case of ovarian and prostate cancers, their classification as homologous recombination repair (HRR) deficient (HRD) or mutated (HRRm) also makes PARPi an available treatment option beyond BRCA1 or BRCA2 mutational status. However, identification of the most relevant genetic alterations driving the HRD phenotype has proven difficult and recent data have shown that other genetic alterations not affecting HRR are also capable of driving PARPi responses. To gain insight into the genetics driving PARPi sensitivity, we performed CRISPR-Cas9 loss-of-function screens in 6 PARPi-insensitive cell lines and combined the output with published PARPi datasets from 8 additional cell lines. Ensuing exploration of the data identified 110 genes whose inactivation is strongly linked to sensitivity to PARPi. Parallel cell line generation of isogenic gene knockouts in ovarian and prostate cancer cell lines identified that inactivation of core HRR factors is required for driving in vitro PARPi responses comparable to the ones observed for BRCA1 or BRCA2 mutations. Moreover, pan-cancer genetic, transcriptomic and epigenetic data analyses of these 110 genes highlight the ones most frequently inactivated in tumours, making this study a valuable resource for prospective identification of potential PARPi-responsive patient populations. Importantly, our investigations uncover XRCC3 gene silencing as a potential new prognostic biomarker of PARPi sensitivity in prostate cancer. Statement of significanceThis study identifies tumour genetic backgrounds where to expand the use of PARP inhibitors beyond mutations in BRCA1 or BRCA2. This is achieved by combining the output of unbiased genome-wide loss-of-function CRISPR-Cas9 genetic screens with bioinformatics analysis of biallelic losses of the identified genes in public tumour datasets, unveiling loss of the DNA repair gene XRCC3 as a potential biomarker of PARP inhibitor sensitivity in prostate cancer.

cancer biology↗

bioRxiv2020

SLFN11 captures cancer-immunity interactions associated with platinum sensitivity in ovarian cancer

Large independent analyses on cancer cell lines followed by functional studies have identified Schlafen 11 (SLFN11), a putative DNA/RNA helicase, as the strongest predictor of sensitivity to DNA-damaging agents. However, its role as a prognostic biomarker is undefined, partially due to the lack of validated methods to score SLFN11 in human tissues. Here, we implemented a pipeline to quantify SLFN11 in human cancer samples. By analyzing a cohort of high-grade serous ovarian carcinoma specimens prior platinum-based chemotherapy treatment, we demonstrate that SLFN11 is expressed by infiltrating innate and adaptive immune cells. We show, for the first time, that SLFN11 density in both the neoplastic and microenvironmental components was independently associated with favorable outcome. Transcriptomic analyses suggested the presence of a hitherto modulation of the cancer-immunity cycle orchestrated by SLFN11. We propose SLFN11 as a dual biomarker capturing simultaneously interconnected immunological and cancercell-intrinsic functional dispositions associated with sensitivity to DNA damaging agents.

cancer biology↗