Francisco J. Esteva: The clinical applications of PARPi across various cancers / Arshit Narang, Breast Cancer, cancer, Chadi Hage Chehade, Francisco J.

Abstract. Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat BRCA1/2 mutant cancers. Although PARPi sensitivity has been at

The tumour-suppressor protein BRCA2 is discovered to have a previously undescribed role in maintaining genomic integrity and the sensitivity of PARP1 inhibitors.

PARP inhibitor treatment triggers histone release from the chromatin in cancer cells; consequently, targeting the histone chaperone NASP renders cells vulnerable to PARP inhibition.

Abstract. Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPis) are currently used to treat BRCA1/2 mutant cancers. Although PARPi sensitivity has been at

Nature Cell Biology - PARP inhibitors kill cancer cells by trapping poly(ADP-ribose) polymerase 1 (PARP1) on DNA. A study now shows that cancer cells use a specialized form of autophagy to extract...

The poly(ADP-ribose) polymerase inhibitor (PARPi) class of drugs represents a remarkable advance in the treatment of patients with homologous recombination-deficient tumours, but resistance remains a challenge1–5. Although most research has focused on the downstream consequences of PARPi exposure to tackle resistance, the immediate effect of PARP inhibition on the chromatin environment and its contribution to PARPi toxicity remains elusive. Here we show that PARP inhibition induces histone release from the chromatin. This presents a vulnerability of PARPi-resistant cancer cells, which require histone homeostasis mechanisms to sustain elevated DNA replication rates and survival. Through functional genetic screens, we identified NASP as a key factor in maintaining the stability of evicted histones via its TPR motifs. Loss of NASP renders tumour cells hypersensitive to PARPi treatment in vitro and in vivo, impairs replication fork progression and elevates levels of replication-a

Toxicities limit combination of PARP inhibitors (PARPi) and chemotherapy in patients with germline BRCA1 and BRCA2 pathogenic variant (gBRCAm) breast cancer. Here, the authors report a preclinical study followed by a randomised phase II/III clinical trial investigating the addition of a gap between chemotherapy (carboplatin and paclitaxel) and PARPi (olaparib), in patients with early gBRCAm breast cancer.

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxicity in homologous recombination repair (HR)-deficient (HRD) cancers by trapping PARP1 on chromatin, thereby causing irreparable replication-associated DNA damage. Although increased clearance of trapped PARP1 from chromatin reduces the sensitivity of cancer cells to PARPi, details surrounding this process remain unclear. PARPi exposure is known to cause increased autophagy flux, whereas autophagy inhibition can hypersensitize cells to PARPi. Our study reveals that trapped PARP1 is cleared via nucleophagy, with the selective autophagy receptor TEX264 and its partner segregase p97 (also known as VCP) orchestrating this process. TEX264 interacts directly with trapped PARP1, linking it to the autophagosomal protein LC3 for degradation. Disrupting this pathway, either chemically or genetically, increases PARP1 trapping, resulting in protein aggregates, DNA damage and cell lethality, ultimately re-sensitizing PARPi-resista