Lysosomes Are Why Your Cancer Drug May Not Work

When two ovarian cancer patients get the same dose of the same drug, you would expect similar outcomes. Often you do not get them. A study out this month from the MRC Laboratory of Medical Sciences (LMS) and Imperial College London, published in Nature Communications, offers one reason why — and it is hiding in the lysosome.

Lysosomes are the cell's recycling centers, pockets of acidic fluid that break down worn-out proteins and other debris. The team, led by Dr. Louise Fets, who runs the Drug Transport and Tumour Metabolism Group at the MRC LMS, found that two widely used PARP inhibitors — rucaparib and niraparib — get pulled into these compartments and trapped there. Instead of spreading evenly through the cell, they pool in lysosomal reservoirs, slowly releasing over time. This creates wide variability in drug levels from cell to cell, even within the same tumor. Cells that accumulate more drug respond more; those that accumulate less may survive.

Olaparib, the market leader, behaves differently. It does not get trapped. Its lipophilicity stays stable across the pH range it encounters inside a cell, so it diffuses through the cytoplasm rather than pooling in lysosomes. This is not necessarily better or worse — the slow-release effect from lysosomal trapping may actually increase total drug exposure in some cells — but it does mean olaparib's distribution is more uniform.

The researchers used a technique that is not standard in most pharmacology studies: mass spectrometry imaging combined with spatial transcriptomics, applied directly to patient tumor tissue. They took thin slices of ovarian cancer samples — obtained from patients undergoing cytoreductive surgery at Hammersmith Hospital, performed by Professor Christina Fotopoulou — and kept the tissue alive in a patient-derived explant culture system (established by Dr. Paula Cunnea). They then treated the explants with PARP inhibitors and mapped exactly where the drugs ended up at single-cell resolution.

What they saw surprised them. "We were surprised to see large variability in drug accumulation at the single-cell level," said Dr. Carmen Ramirez Moncayo, the paper's first author and a postdoctoral researcher at the MRC LMS. "This variability was driven by the build-up of a drug in lysosomes, which are acting as reservoirs, increasing the exposure of cancer cells to drugs, by storing and releasing the drug when needed."

The finding connects to one of oncology's most persistent problems. PARP inhibitors have transformed care for ovarian, breast, and prostate cancers — but a substantial fraction of patients do not respond initially, and many who do eventually develop resistance. Standard explanations focus on mechanisms that pump drugs out of cancer cells, like BRCA reversion mutations or ABC transporter overexpression. This work points to something earlier in the chain: uneven drug delivery at the single-cell level, before drugs even reach their targets, according to ScienceDaily.

The three FDA-approved PARP inhibitors — olaparib, rucaparib, and niraparib — do not behave identically inside cells. Olaparib and niraparib remain FDA-approved for ovarian cancer; rucaparib's US indication was withdrawn in June 2022. But the lysosomal trapping effect appears to affect rucaparib and niraparib but not olaparib, and that difference in intracellular behavior may matter when choosing which drug to give a patient — a question the researchers argue is worth studying clinically, not a settled conclusion.

The study also used spatial transcriptomics to look at gene expression in high-drug versus low-drug regions of the same tissue slice. That gave them a molecular readout of what the heterogeneity actually means functionally — not just where the drug goes, but what changes in cells that get less of it.

The work is early: it was done in explants, not in patients receiving treatment, and the lysosomal trapping effect was demonstrated with acute dosing. What happens during the multi-cycle regimens used clinically, where drugs are given repeatedly over months, is not yet known. The team plans to study animal models and larger patient cohorts to see how lysosomal storage, tumor vasculature, and drug delivery interact in relapsed disease. That is the right next step, and it will take time.

What is clinically actionable right now is limited — none of this changes which drug a physician reaches for tomorrow. But the findings open a door: if lysosomal content and pH affect how much drug actually reaches its target inside individual cells, then measuring those features in a patient's tumor before treatment might help predict who will respond and who will not. "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," Fets said, "Eventually, we hope to be able study the molecular signature of a patient's tumor to help to tailor therapeutic approaches in a more personalized way."

The study was funded in part by a Victoria's Secret Global Fund for Women's Cancers Career Development Award, in partnership with Pelotonia and the American Association for Cancer Research. The paper declares that senior author Iain McNeish has undertaken advisory boards for AstraZeneca, Clovis Oncology, and GSK, and that Imperial College London has received institutional grant support from AstraZeneca; olaparib (Lynparza) is an AstraZeneca product. Mass spectrometry proteomics data are available via the ProteomeXchange Consortium (PXD057265), spatial transcriptomics via GEO (GSE281519), and code on Zenodo.