NASP histone turnover ties PARPi resistance

A new study shows PARP inhibition triggers histone eviction from chromatin and NASP helps maintain histone balance, revealing a potential target to overcome PARP inhibitor resistance.

NASP modulates histone turnover to drive PARP inhibitor resistance

PARP inhibitors have transformed treatment for homologous recombination deficient cancers, but resistance remains a hurdle. A new study shows that PARP inhibition triggers histone eviction from chromatin, revealing a vulnerability in PARPi resistant cells that rely on histone supply pathways to sustain high DNA replication rates. The researchers used genetic screens to identify NASP as a key histone chaperone that stabilizes evicted histones through its TPR motifs. They found that removing NASP makes tumor cells hypersensitive to PARPi in lab dishes and animal models, disrupts replication fork progression, and raises replication-associated DNA damage. NASP appears to work with the INO80 remodeling complex and PARP1’s chaperone activity to balance histone turnover and prevent lethal damage. The work positions histone eviction as an immediate cellular response to PARPi and suggests that targeting histone supply could help overcome resistance.

Despite the promise, translating these insights into patient care will require careful testing. Histone supply pathways are active in normal cells too, so therapies must spare healthy tissue. The study frames a new therapeutic angle that could complement existing strategies like PARP inhibitors and polymerase theta inhibitors. If confirmed in further studies, doctors may gain a new lever to prevent or delay resistance and researchers may explore drug combinations that disrupt histone turnover in tumors.

The finding shifts attention to the early chromatin changes induced by PARP inhibitors rather than their later effects. Showing histone eviction as a direct response suggests a second set of targets in the chromatin repair machinery. Targeting NASP or the INO80-PARP1 axis could create a synthetic vulnerability, but it also challenges researchers to navigate potential effects on normal cells during DNA replication.

This work fits a broader trend in cancer therapy: resistance often hinges on fine cellular balances. Tumors that survive PARPi may rely on precise histone dynamics and chromatin remodeling; disrupting these dynamics could restore sensitivity. Real-world use will demand biomarkers to identify patients who benefit and rigorous safety testing to avoid collateral damage in healthy tissue.

Highlights

The chromatin story is only starting to unfold and will test its clinical potential in the years ahead.