Can Chemo-Resistant Cancer Cells Be Resensitized?
Summary
- Sylvester Comprehensive Cancer Center scientists uncovered a new cellular stress state triggered when transcription continues despite DNA damage — a process enabled by blocking p300.
- This runaway transcriptional activity overwhelms the cell’s protein‑folding machinery, creating internal stress that becomes lethal when platinum-based chemotherapy is combined with impaired p300 function.
- Targeting p300 re-sensitizes drug-resistant tumors, revealing an encouraging therapeutic strategy for cancers that no longer respond to cisplatin or related agents.
When cells are struck by something damaging—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.
Now, researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, have discovered a surprising way to use that stubbornness against cancer cells. Their findings are published in Genes & Development.
Their new study uncovers how blocking a key protein, p300, forces damaged cancer cells into a state of uncontrolled transcriptional activity. This creates a novel form of cellular stress that can make even chemo-resistant tumors sensitive again to treatment.
“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,” said Ramiro Verdun, Ph.D., a research professor in the Division of Hematology at Sylvester.
Cells are constantly reading DNA and making proteins, a choreography so precise it resembles a symphony orchestra following a score. When DNA is damaged, that score becomes unreadable. So, the cell performs an essential function. It pauses the music until repairs are made.
The pause protects the cell from copying or translating damaged instructions, and several molecular players, including p300, orchestrate it. 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,” said Dr. Verdun. “When the DNA script is damaged, the cell is supposed to deal with the problem before pushing forward.”
But the Sylvester team discovered that when p300 is inhibited, the traffic officer fails to clear the accident. Stalled transcription machinery lingers and cells keep forcing transcription through damaged DNA.
A Factory Running at Full Speed With Broken Machinery
Without p300, cells keep reading DNA and producing proteins even when the DNA is damaged. It’s like running a factory at full speed while conveyor belts buckle, machines spark and raw materials are warped.
Inside the cell, this creates a flood of newly made proteins, many of them misfolded or unstable, leading to a buildup of toxic protein “clutter” and intense stress inside the endoplasmic reticulum — the cell’s protein-folding workshop. The cell’s internal quality‑control system — the unfolded protein response — lights up like an alarm panel.
The stress becomes overwhelming, like an engine overheating after being pushed too hard for too long.
Turning a Cancer Cell’s Strength Into Its Weakness
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 intensely 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 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.
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.
Dr. Ramin Shiekhattar
“It is the biological equivalent of overloading a faulty circuit, not by increasing DNA damage, but by bypassing the cancer’s usual resistance response,” said Dr. Verdun. “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.
A New Strategy for Chemoresistant Tumors
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 the possibility of 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.
“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 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.”
Why This Discovery Matters
The team, which included Sylvester researchers Carolina P. Bañuelos, Ph.D., Lucas D. Caeiro, Ph.D., Pradeepkumar R. Cingaram, Ph.D., and faculty members Felipe Beckedorff, Ph.D., an assistant professor in the Dr. John T. Macdonald Foundation Department of Human Genetics, Daniel Bilbao Cortes, Ph.D., M.B.A., an associate professor of pathology and laboratory medicine, and Lluis Morey, Ph.D., an associate professor in the Dr. John T. Macdonald Foundation Department of Human Genetics, in addition to Drs. Verdun and Shiekhattar, exposed a stress pathway that had not been tapped before.
When cells keep working 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.
“For patients whose tumors have stopped responding to chemotherapy, this gives us a way to make those treatments meaningful again,” said Dr. Morey. “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.”
By discovering that refusal and the chaos it triggers, Sylvester researchers have revealed a new way that may help to push back against cancer’s most resilient forms.
Tags: cancer epigenetics, Cancer Epigenetics Program, cancer research, chemotherapy, Division of Hematology, Dr. Daniel Bilbao Cortes, Dr. Felipe Beckedorff, Dr. John T. Macdonald Foundation Department of Human Genetics, Dr. Lluis Morey, Dr. Ramin Shiekhattar, Dr. Ramiro Verdun, epigenetics, genomics, hematology, Newsroom, Sylverster Comprehensive Cancer Center