Chromatin adaptation and histone remodeling as mechanisms of PARP inhibitor resistance and therapeutic vulnerability.

Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of homologous recombination (HR)-deficient tumors. Nevertheless, their clinical utility is often compromised by the emergence of resistance. Although genetic restoration of HR is a well-established resistance mechanism, emerging evidence suggests that epigenetic and chromatin responses are also central determinants of cell survival under PARPi-induced stress. Indeed, PARP inhibition drives the acute depletion of H3-H4 histones, thereby creating a cellular reliance on efficient histone recycling to ensure genome integrity. The histone chaperone Nuclear Autoantigenic Sperm Protein (NASP) has recently been implicated as a critical regulator in this process by sequestering evicted histones from degradation and promoting chromatin recovery. This NASP-dependent histone turnover may be particularly relevant to cancer stem cell (CSC) biology, as CSCs rely on dynamic chromatin plasticity to switch between phenotypic states and resist therapy. In this review, we focus on the intersection of histone dynamics and CSC survival, with particular emphasis on the ATP-dependent chromatin remodeler inositol-requiring mutant 80 (INO80), the NASP histone maintenance axis, and histone chaperones such as Facilitates Chromatin Transcription (FACT) as potential therapeutic targets. Targeting these chromatin maintenance pathways may provide new opportunities to overcome PARPi resistance and limit the persistence of resistant CSC subpopulations, although further experimental validation is required.