HMN 2026: How Hidden drug reservoirs in cancer cells could explain treatment resistance

One of oncology’s biggest challenges is that the same treatment can work well for some patients but fail completely in others. A study published in Nature Communications, by a multidisciplinary team led by Dr. Louise Fets at the LMS, has mapped the distribution of a type of targeted treatment, known as PARP inhibitors, using advanced imaging techniques and patient ovarian tumor samples. The research reveals that the buildup of these drugs in lysosomes—small compartments inside cells that normally act as “recycling centers”—can trap and release certain drugs over time, shaping how well treatments work.

Mapping drug delivery

Cancer treatment options have increased exponentially in recent years, significantly improving patient prognosis. For ovarian cancer patients, this revolution has come in the form of a group of drugs called PARP inhibitors. However, some patients do not respond to treatment, while others develop resistance over time. For a drug to be effective, it must build up in cancer cells at sufficient levels to trigger cell death. Despite its importance, drug distribution within tumors, and the mechanisms that regulate this, are poorly understood.

This study shows that the problem isn’t just whether a drug reaches a tumor, but how it spreads within the tumor and inside its cells. The researchers used thin slices of ovarian tumors taken from patients and kept alive in the lab. These tumor “explants” were treated with PARP inhibitors, allowing the team to directly observe how drugs spread through real human tumor tissue.

Using mass spectrometry imaging, the team created high-resolution maps showing exactly where drug molecules accumulated. They combined this with spatial transcriptomics, which allowed them to compare gene activity in regions with high and low drug levels, all within the same tissue sample. The results showed drug levels varied dramatically across different regions of the same tumor and between patients, even when the same drug dose was used.

“A novel aspect of this study was the use of mass spectrometry imaging to directly measure and visualize drug uptake in patient tumor tissue. Through the spatial mapping of drug molecules, we could pinpoint regions of high and low drug and compare gene expression, from the same tissue slice, using spatial transcriptomics,” says Dr. Zoe Hall, senior author and Associate Professor at Imperial’s Department of Metabolism, Digestion and Reproduction.

Lysosomes: The cell’s hidden drug storehouses

The team discovered that the uneven drug distribution was driven by lysosomes. Some PARP inhibitors were being pulled into lysosomes and stored there. Instead of spreading evenly through the cell, the drugs became trapped in these compartments, creating internal drug reservoirs.

These lysosomal reservoirs act like slow-release stores—holding the drug and releasing it over time—which increases exposure in some cells, while leaving others relatively unexposed. To further complicate matters, not all PARP inhibitors behave the same way. The study found that this lysosomal storage mechanism applies to some drugs, such as rucaparib and niraparib, but not others like olaparib.

“We were surprised to see large variability in drug accumulation at the single-cell level. 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,” says Dr. Carmen Ramirez Moncayo, first author and a postdoctoral researcher at the LMS.

The future of cancer treatment

PARP inhibitors are already widely used in ovarian, breast and prostate cancer treatments, and are in clinical trials for many other cancers. Understanding how drugs are stored and distributed in cells could ultimately open the door to more personalized treatment strategies that improve success rates 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. Eventually, we hope to be able to study the molecular signature of a patient’s tumor to help to tailor therapeutic approaches in a more personalized way,” says Dr. Fets, senior author and head of the LMS’s Drug Transport and Tumor Metabolism Group.

This study used patient tumor tissue maintained outside the body. In real patients, drugs are delivered through the bloodstream, and tumor blood vessels are often disorganized, which may further increase uneven drug delivery. Future research will use animal models and larger patient studies to better understand how drug delivery, tumor structure and lysosomal storage interact in real clinical settings, including in relapsed cancers.

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