Kierkegaard observed that one of humanity’s enduring tensions is that while life can only be understood backwards, it must be lived forwards. It’s a truth medicine knows intimately: in the treatment that worked until it didn’t, the resistance that arrived without warning, the moment a doctor has to tell a patient that the drug that was helping has stopped. Not because anyone made a mistake, but because the critical knowledge that would have mattered arrived too late, if at all.
A recent paper from the National Cancer Institute is, in a small but meaningful way, science’s pursuit of that elusive foresight: an understanding that emerges early enough, for once, to change what happens next.
The Elegant Idea
For decades, chemotherapy has worked by brute force, flooding the body with toxins designed to kill rapidly dividing cells. The problem is that rapid division isn’t unique to cancer. Hair follicle cells, gut lining cells and immune cells also divide rapidly, which is why patients lose hair, lose energy and become susceptible to infection. Chemotherapy targets a behavior, but the drug has no way to tell a healthy cell from a cancerous one.
Antibody-drug conjugates (ADCs) change that. Instead of targeting what cancer cells do, they target what cancer cells are. Cancer cells tend to display certain proteins on their surface in far greater numbers than healthy cells do. The antibody is engineered to seek out those proteins specifically. It navigates to its target, binds and waits for the cell to do what cells routinely do: pull it inside. Once there, the cell’s own digestive machinery (the lysosome) breaks down the chemical tether holding the toxin to the antibody, releasing the toxin to kill the cell from within. More than a dozen ADCs have received FDA approval in recent years, and the field is evolving fast.
What the Cell Does Next
But cancer cells don’t simply accept their fate. Even when an ADC delivers its payload perfectly—the antibody finds its target, the cell pulls it inside, the lysosome cuts the tether—a pump embedded in the cell membrane can grab the released toxin and throw it back out before it causes damage.
The delivery worked. The package got ejected anyway.
These pumps—ATP-binding cassette transporters, or more plainly, efflux pumps—are a normal feature of cell biology. Their job is cellular housekeeping, clearing out unwanted or toxic substances before they cause damage. Under the pressure of drug treatment, cancer cells do what life has always done under pressure: the ones best equipped to survive do. The same mechanism that has shaped living things for billions of years now works against the treatment. Not all cancer cells are identical, and the ones that happen to produce more pumps survive while others don’t, gradually shifting the tumor toward resistance.
Better on Both Counts
Efflux pumps are a focus because they represent a rare case: a resistance mechanism that can be addressed before a drug ever reaches a patient. What the NCI researchers set out to do was draw a map of payload vulnerability before resistance drew it for them, as it otherwise would, one patient’s resistant tumor at a time. They screened 27 toxins commonly used as ADC payloads against the efflux pumps known to drive treatment resistance, identifying which ones the pumps could eject and which ones they couldn’t. Among the findings: some of the payloads most susceptible to ejection were already in FDA-approved drugs.
The study didn’t only deliver bad news, though. The pumps couldn’t eject other payloads, and those same payloads happened to be among the most potent cell killers in the entire panel, tested across 99 cancer cell lines. The pump-proof options weren’t a lukewarm compromise. They were better on both counts and closed off the very mechanism that natural selection would otherwise reward.
The map the NCI researchers produced has also proven immediate value. While next-generation ADCs are still being built, researchers studying resistance in metastatic breast cancer have already found that switching to a different ADC—one whose payload the pumps can’t eject—can restore treatment effectiveness.
The Question Asked a Thousand Times
Research like this depends on being able to ask the same question thousands of times with precision: did this payload kill these cells, or didn’t it? To answer that across 27 payloads and dozens of cell line comparisons, the team relied on the CellTiter-Glo® Luminescent Cell Viability Assay, turning what might otherwise have taken years into a single study.
This luminescent assay measured ATP (the energy molecule living cells produce and dead cells don’t) to give a reliable readout of whether cells survived their encounter with a given payload. The CellTiter-Glo® Assay has become the standard for this kind of work not because it’s the only option, but because of its simplicity. Its single-reagent, add-mix-measure protocol maintains accuracy across thousands of wells without introducing the unreliability that multi-step protocols would. Without it, the map doesn’t get drawn.
Knowledge That Arrives in Time
The contribution here isn’t a new drug but a new starting point. The most important decisions about ADCs, which payloads to build and which to avoid, used to get made after resistance had already emerged in patients. This research moves the decisions upstream: from the clinic to the design table, from a patient in treatment to a drug not yet built.
Kierkegaard’s dilemma is binary: the understanding either arrives in time or it doesn’t. For much of cancer medicine’s history, it hasn’t. This research is genuine proof that understanding can arrive first. Before the first dose.
Sources
Roth JS, Guo H, Chen L, et al. Identification of antibody-drug conjugate payloads which are substrates of ATP-binding cassette drug efflux transporters. bioRxiv. 2025. https://doi.org/10.1101/2025.05.22.651305
Payload Diversification Overcomes Resistance and Guides Sequential Antibody-Drug Conjugate Therapy in Breast Cancer. Clinical Cancer Research. 2026. https://aacrjournals.org/clincancerres/article-abstract/doi/10.1158/1078-0432.CCR-25-3321
CellTiter-Glo Luminescent Cell Viability Assay. Promega Corporation. https://www.promega.com/products/cell-health-assays/cell-viability-and-cytotoxicity-assays/celltiter_glo-luminescent-cell-viability-assay/
Elise Johnson
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