PARP inhibitors (PARPi) have transformed the treatment of hereditary BRCA1/2-mutated breast cancers. These drugs use a clever concept called synthetic lethality: the cancer’s BRCA1/2 mutation alone isn’t fatal, and PARPi alone doesn’t kill cells - but together, they specifically wipe out cancer cells while sparing healthy ones.
PARP inhibitors (PARPi) have transformed the treatment of hereditary BRCA1/2-mutated breast cancers. These drugs use a clever concept called synthetic lethality: the cancer’s BRCA1/2 mutation alone isn’t fatal, and PARPi alone doesn’t kill cells - but together, they specifically wipe out cancer cells while sparing healthy ones.
The problem? Many cancers eventually become resistant to PARPi, limiting their long-term benefit. Now, researchers from the lab of Oncode Investigator Jos Jonkers, in collaboration with Oncode Investigators Thijn Brummelkamp and Lodewyk Wessels (all at the Netherlands Cancer Institute), have uncovered a surprising vulnerability in drug-resistant cancer cells. Their findings, published in Nature, reveal how disrupting the cell’s “histone supply chain” could make even resistant cancers sensitive to treatment again.
Overcoming cancer's resistance: uncovering a hidden weakness in PARP-resistant cancers
Histones on the Move
Until now, scientists thought PARPi worked mainly by causing DNA breaks. But the team discovered that PARPi have an immediate and unexpected effect: they disrupt the way DNA is packaged by evicting histones - the spool-like proteins that DNA wraps around for protection and structure.
Once histones are removed, the cell relies on a tightly managed recycling system to keep them safe and put them back. The INO80 complex pulls histones off DNA, NASP stores them until they are needed, and PARP1 helps reincorporate them into the DNA structure.
“Cancer cells heavily rely on this INO80-NASP-PARP1 axis to meet their increased demand for histones, particularly under high rates of DNA replication and DNA damage induced by chemotherapeutics,” explained Oncode Researcher Abdel Mazouzi, postdoctoral fellow in Thijn Brummelkamp’s lab and co-corresponding author of this study.
Breaking the Chain to Break Resistance
When NASP is missing, this recycling chain collapses. Histones pile up in the wrong places, DNA damage accumulates, and cancer cells - whether PARPi-naïve or already resistant - become hypersensitive to the drug.
“This is a vulnerability we didn’t know existed,” says Oncode Researcher and lead author Sarah Moser. “By disrupting histone recycling, we can push even resistant cancer cells past their breaking point.”
Impact: A New Way to Boost Cancer Treatment
In both cell and mouse models, removing NASP restored PARPi sensitivity and slowed cancer growth. Targeting this histone supply chain could extend the effectiveness of PARPi therapy, offering patients with stubborn cancers more treatment options and more time before resistance develops.
This discovery highlights how deep molecular insights can lead to smarter, more durable cancer treatments - and offers fresh hope for tackling one of oncology’s toughest challenges.