Lysosomes Shape How PARP Inhibitors Work in Ovarian Cancer

One of oncology’s major challenges is that the same treatment can be highly effective for some patients yet fail in others. A study in Nature Communications from a multidisciplinary team led by Louise Fets at the Medical Research Council Laboratory of Medical Sciences examined why a class of targeted treatments, PARP inhibitors, can have such variable effects in ovarian cancer. Using advanced imaging approaches and patient ovarian tumor samples, the researchers mapped where these drugs accumulate inside tumors and discovered that lysosomes—small cellular compartments that act as “recycling centers”—can trap and release certain drugs over time, influencing treatment effectiveness.

Cancer treatment options have expanded rapidly and have improved outcomes for many people, including those with ovarian cancer, where PARP inhibitors have become an important therapy. Yet some patients do not respond, and others develop resistance. For a drug to work, it must reach and build up in cancer cells at levels sufficient to trigger cell death, but drug distribution within tumors and the mechanisms that regulate it are not well understood. This work shows that the key issue is not only whether a drug reaches a tumor, but also how it spreads within the tumor and inside individual cells.

The team used thin slices of patient ovarian tumors, kept alive in the lab as tumor “explants,” and treated them with PARP inhibitors to watch how the drugs spread through real human tissue. Mass spectrometry imaging produced high-resolution maps showing exactly where drug molecules built up. When combined with spatial transcriptomics, the researchers could compare gene activity in regions with high and low drug levels within the same sample. Drug levels varied markedly across different tumour regions and between patients given the same dose. “A novel aspect of this study was the use of mass spectrometry imaging to directly measure and visualize drug uptake in patient tumor tissue…,” said senior author Zoe Hall, who highlighted how spatial mapping allowed comparison of drug distribution and gene expression from the same tissue slice.

They found that lysosomes drove much of this uneven distribution. Some PARP inhibitors were drawn into lysosomes and stored there, forming internal drug reservoirs. These reservoirs acted as slow-release stores, increasing drug exposure in some cells and leaving others relatively unexposed. Not all PARP inhibitors behaved similarly: lysosomal storage was seen for drugs such as rucaparib and niraparib, but not for olaparib. “We were surprised to see large variability in drug accumulation at the single-cell level…,” added first author Carmen Ramirez Moncayo, explaining that lysosomes act as reservoirs, storing and releasing drug.

Because PARP inhibitors are already widely used in ovarian, breast, and prostate cancers and are in trials for other cancers, understanding cellular drug storage and distribution could support more personalized treatment strategies that improve success and reduce resistance or relapse. “By understanding how drugs are taken up into cells, we can understand whether this influences why cancer drugs work for some people and not for others,” said co-author Louise Fets, who hopes tumor molecular signatures could eventually help tailor therapy.