Biology subjects

Illuzzi, G.

Publications and source records attributed to Illuzzi, G..

3 recordsLinked to original sources

bioRxiv2026

The EGFR inhibitor osimertinib promotes a dynamic Drug Tolerant Persister state marked by replication defects and genome instability

Osimertinib is the current standard-of-care for treatment-naive patients with EGFR mutation-positive advanced/metastatic non-small cell lung cancer (NSCLC), however resistance inevitably emerges. Osimertinib does not eradicate all cancer cells even in culture, leaving a long-lasting sub-population of Drug Tolerant Persister (DTP) cells that is common to many chemotherapeutics. The DTP population is non-proliferative and seemingly dormant, but resistant clones eventually emerge from the DTP state. Here we show that extensive DNA replication occurs in the DTP state and cells frequently progress through the cell cycle, though cell death is also frequent, such that cell division and cell loss are balanced and the population remains approximately constant. Cell cycling occurs with aberrant gene expression and abnormal DNA replication pattern, leading to DNA damage, extrachromosomal circular DNA formation and mitotic defects, such that replicating DTP cells are hypersensitive to low doses of ATM and ATR inhibitors. Our findings suggest that the DTP state is highly mutagenic and that targeting DNA repair in DTP cells has the potential to prevent the emergence of resistance through de novo mutations.

Cancer Biology↗

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↗