Study: Blocking a Key Protein May Re-Sensitize Chemo-Resistant Tumor

Overcoming tumor resistance to chemotherapy drugs has long been a challenge for oncology clinicians and researchers. Now, a new study suggests that blocking a key protein, acetyltransferase p300, may force damaged cancer cells into a state of uncontrolled transcriptional activity, thereby creating a novel form of cellular stress that can make even chemo-resistant tumors sensitive again to treatment.

The study, led by researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, appears online in the February 6, 2026, edition of the journal Genes & Development.

Cool down and repair
When cells are struck by something damaging, such as, for example, ultraviolet light, environmental exposures, or chemotherapy, they’re supposed to do something simple and wise: stop and assess the damage. It’s a biological version of pulling over when your engine light flashes, giving your system a chance to cool down and repair.

But cancer cells don’t always follow the rules. Many learn to keep pushing forward by rapidly adapting—rerouting drugs, rewiring repair pathways, and clearing damage more efficiently—allowing tumors to become resistant to chemotherapy, the very drugs meant to stop them.

“It’s a fresh angle on the long-standing problem of chemotherapy resistance, and an encouraging path toward restoring the power of widely used chemotherapy drugs,” explained Ramiro Verdun, Ph.D., Sylvester research professor in the Division of Hematology.

Cells constantly read DNA and make proteins, but when DNA is damaged, the cell pauses to repair it.

The pause protects the cell from copying or translating damaged instructions, and several molecular players, including acetyltransferase p300, orchestrate it. Acetyltransferase p300 is a critical human histone acetyltransferase and transcriptional coactivator that regulates gene expression by acetylating histones and transcription factors.[1]

As a key epigenetic regulator, it controls cell proliferation, differentiation, and apoptosis, and is also frequently a tumor promoter in various cancers.

Think of p300 as a traffic officer at the site of an accident: when damage occurs, p300 steps in to clear stalled transcription machinery so traffic can be properly managed again.

“It’s one of the most basic safety checks a cell has,” Verdun explained.

“When the DNA script is damaged, the cell is supposed to deal with the problem before pushing forward,” he added.

Stalled transcription
But the Sylvester team discovered that when acetyltransferase p300 is inhibited, the traffic officer fails to clear the accident. Stalled transcription machinery lingers, and cells keep forcing transcription through damaged DNA. In a study, they identified acetyltransferase p300 as a key regulator of transcription-coupled nucleotide excision repair (TC-NER-) dependent RNA polymerase II (RNAPII) removal from damaged chromatin via a USP7-dependent mechanism.

The researchers observed that without acetyltransferase p300, cells continue to read DNA and produce proteins even when the DNA is damaged. In essence, the loss of the acetyltransferase p300 allows RNAPII to ‘bypass’ transcription-blocking lesions, thereby sustaining transcription and full-length mRNA production despite DNA damage.

Inside the cell, this creates a flood of newly made proteins—leading to many misfolded or unstable proteins. In turn, this leads to a buildup of toxic protein ‘clutter’ and intense stress in the endoplasmic reticulum (ER)—the cell’s protein-folding workshop. This activates the unfolded protein response (UPR)—the cell’s internal quality‑control system —which compromises cell viability.

Stress
The stress becomes overwhelming, like an engine overheating after being pushed too hard for too long. But here’s the twist: This meltdown becomes a vulnerability. Tumors that resist platinum therapy often survive by tolerating DNA damage. But this study shows that when p300 is blocked, those same tumors become highly sensitive again—not because their DNA is more damaged, but because they can’t handle the stress of pushing through it.

In lab models and patient-derived xenografts, platinum chemotherapy alone had a limited effect, and blocking p300 alone had only a modest impact. However, when combined, they produced a strong synergistic effect that selectively eliminated tumor cells.

“It is the biological equivalent of overloading a faulty circuit—not by increasing DNA damage, but by bypassing the cancer’s usual resistance response,” Verdun noted.

“These cells can cope with cisplatin-damaged DNA, but they can’t cope with the sudden and intense protein stress that builds up when transcription keeps going,” he further explained.

Major limits
Platinum-based chemotherapies face two major limits in the clinic: tumors often become resistant, and even when they respond, toxicity to normal tissues—particularly the kidneys and nervous system—can force doctors to reduce doses or stop treatment altogether.

This work opens a new door: Instead of increasing chemotherapy intensity, make the cancer more vulnerable to the dose patients can already tolerate. By shifting how tumor cells respond to damage, blocking p300 turns that principle into a practical therapeutic approach.

In two chemo-refractory patient-derived models—colorectal cancer and pediatric osteosarcoma—the combination shrank tumors and improved survival.

Rethinking treatment options
“What excites us most is the opportunity this creates to rethink treatment for patients who’ve run out of options,” said Ramin Shiekhattar, Ph.D., co-leader of the Cancer Epigenetics Program at Sylvester, chief of the Division of Cancer Genomics and Epigenomics, and the Eugenia J. Dodson Chair in Cancer Research.

“By uncovering this stress state, we can begin to design smarter combinations that anticipate resistance rather than simply react to it, with the long-term goal of making standard chemotherapies work longer and for more people,” Shiekhattar said.

Blocking p300
The team exposed a stress pathway that had not been tapped before. When cells continue to function despite DNA damage, they enter a state of unresolved internal stress that can be therapeutically exploited. The research also identifies p300 as a new target in drug-resistant cancers: blocking this protein prevents proper resolution of stalled transcription, pushing tumor cells into a stress state that chemotherapy can exploit.

Crucially, the approach offers a way to re-sensitize tumors without adding toxicity. Instead of intensifying chemotherapy, it changes how tumor cells respond to damage. This creates new possibilities for combination therapy, where p300 inhibitors and platinum drugs can be paired in a rational, targeted way.

Reframing the DNA repair story
“For patients whose tumors have stopped responding to chemotherapy, this gives us a way to make those treatments meaningful again,” noted Lluis Morey, Ph.D., associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics.

“This study doesn’t just add a chapter to the DNA repair story — it reframes it. It shows that the danger isn’t only in the damage itself, but in what happens when cells refuse to hit pause,” Morey concluded.

Reference
[1] Bañuelos CP, Caeiro LD, Cingaram PR, Beckedorff F, Morey L, Cortes DB, Shiekhattar R, Verdun RE. Bypass of blocking lesions by RNAPII reveals a novel stress induced by DNA damage. Genes & Dev February 5, 2026, doi:10.1101/gad.353164.125

Featured image: “It’s a fresh angle on the long-standing problem of chemotherapy resistance, and an encouraging path toward restoring the power of widely used chemotherapy drugs,” explained Ramiro Verdun, Ph.D., Sylvester research professor in the Division of Hematology. Photo courtesy: © 2026 Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine. Used with permission.