Pinpointing weaknesses in cancer’s armor
April 21, 2025

For scientists like Dr. Scott Rothbart, the same strategies that cancer cells use to survive also are powerful opportunities for developing new treatments.
But first, scientists need to understand the many ways cancer protects itself — and how those defensive layers interact.
“Designing new cancer strategies is like that old arcade game Whack-A-Mole,” Rothbart explains. “For each vulnerability we identify, cancer has another trick up its sleeve to dodge detection and resist treatment. Our goal is to find ways to treat multiple targets at once so that cancer doesn’t have a chance to rally and try again.”
To find answers, Rothbart and his team are exploring epigenetics, which are biological mechanisms that help ensure the right genetic instructions are used at the right time. Epigenetic errors are widely recognized as key contributors to cancer, alongside more familiar genetic causes such as gene mutations.
Unlike mutations that permanently change the DNA sequence itself, epigenetic alterations can, in theory, be reversed, making them promising targets for treatment.
“Epigenetic cancer therapies hold immense promise, particularly when combined with other treatments like immunotherapies,” Rothbart said. “Fixing the epigenetic errors that contribute to cancer cell survival removes some of their defenses while also making sick cells more susceptible to other cancer medications.”
Finding a weak spot in cancer’s armor
Every cell in the body contains DNA, the genetic manual that comprises the instructions for life. Epigenetic mechanisms ensure that the right instructions are used at the right time. For example, when a cell is damaged beyond repair, epigenetic mechanisms switch on genes that shut it down.
Cancer hijacks this epigenetic system to promote its own survival. It keeps anti-cancer genes silent while allowing genes that support unchecked cell growth to stay active. Cancers often harbor multiple epigenetic errors, reinforcing each other in a way that makes it difficult to reactivate tumor-fighting genes.
When one epigenetic safeguard fails, another takes its place to compensate, ensuring that cancer’s protective layers remain intact.
Now, a study published in Molecular Cell by Rothbart and his team sheds light on how these interwoven epigenetic layers work together to sustain cancer cell survival. Their findings reveal a potential weak spot that could be leveraged to improve treatment.
“Our findings are exciting because they reveal how these layers work together,” said Yanqing Liu, a Ph.D. student in Rothbart’s lab and the first author of the study. “Our work also suggests new ways to break the cycle, overcome these defenses and improve cancer therapies.”
In healthy cells, two proteins — UHRF1 and DNMT1 — work together to maintain epigenetic marks that keep certain genes switched off. These marks, known as DNA methylation, act like sticky notes that tell the cell which genes should stay silent. In cancer, DNA methylation patterns become scrambled, silencing tumor suppressor genes while leaving harmful pathways active.
Enter DNMT inhibitors, a type of epigenetic drug that treats cancer by targeting DNMT1 and removing incorrectly placed DNA methylation. This enables silenced tumor suppressor genes to turn back on.
But here’s the challenge: when DNMT1 is blocked, UHRF1 steps in to take its place. But instead of working with DNMT1, UHRF1 now works with another protein, SUV39H1, to activate an alternative pathway of protection.
And when both DNMT1 and UHRF1 are blocked? You guessed it. Cancer cells adapt again, this time by activating a third layer of defense helmed by a protein complex called PRC2.
Although cancer’s ability to switch between these protective layers makes it particularly resilient, no system is perfect. Rothbart’s team has discovered a way to disrupt critical communication between epigenetic mechanisms, a discovery that could lead to more effective treatment strategies.
Interrupting cancer cells’ communication to improve treatment
Like other cells in the body, cancer cells communicate to survive. They use chemical and molecular messengers to adjust to environmental changes, evade threats and gather resources like nutrients. These interactions, known as crosstalk, allow different parts of the cell to coordinate their responses.
“Crosstalk is how our cells and their components communicate with each other,” Rothbart explains. “This cellular chatter holds the answers to a lot of our questions. The more we decipher the language of communication, the better we can understand how it works, how things go wrong and how we might fix problems.”
Rothbart’s team reasoned that interrupting crosstalk could disrupt cancer cells’ epigenetic defenses. Results of their study support this idea.
They identified a specific type of crosstalk between two epigenetic marks that helps cancer cells compensate when DNMT1 is blocked. Interfering with this communication pathway could help DNMT inhibitors work more effectively by exploiting a hidden vulnerability in cancer’s multilayered defense system.
“It’s incredibly exciting to know that disrupting this crosstalk significantly enhances the therapeutic effect of DNMT inhibitors,” Liu said. “By reactivating genes that suppress cancer, we can boost the antiproliferative effects of these important medications. This discovery validates the fundamental molecular mechanism we uncovered and highlights its biological and translational relevance, paving the way for improved cancer therapies.”
Improving DNMT inhibitors also presents new opportunities for combining these drugs with other cancer treatments such as immunotherapies. Work by Rothbart and others has showed that DNMT inhibitors prime cancer cells in ways that make them more susceptible to immune surveillance and immunotherapies, which harness the body’s built-in cancer-fighting abilities.
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A phase 1 clinical trial based on their earlier work is being planned. The trial will combine low doses of a DNMT inhibitor with another drug called an EZH2 inhibitor, which fight cancer better together than either drug alone, according to a May 2024 study by Rothbart and collaborators.
“Cancers have a sophisticated set of protection mechanisms but the more complex the system, the more opportunities there are for vulnerabilities,” Rothbart said. “We’re immensely hopeful that this work will help us develop more effective treatment strategies that target multiple weak spots in cancer’s armor.”
Funding Acknowledgments
Research reported in the Molecular Cell study was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award no. R35GM152184 (Rothbart); the National Cancer Institute of the National Institutes of Health under award nos. P50CA254897 (Issa, Jones and Baylin; sub-project 7830, Rothbart), R01CA283463 (Rothbart) and F32CA260116 (Hrit); and the Van Andel Institute–Stand Up To Cancer® Epigenetics Dream Team. Scott Rothbart, Ph.D., was supported by an American Cancer Society Research Scholar Grant RSG-21-031-01-DMC (https://doi.org/10.53354/ACS.RSG-21-031-01-DMC.pc.gr.144230). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders.
Research reported in the May 2024 Science Advances study was supported by the National Cancer Institute of the National Institutes of Health under award nos. P50CA254897 (Issa, Baylin and Jones; sub-project 7830, Rothbart) and F32CA225043 (Chomiak); and the National Institute of General Medical Sciences of the National Institutes of Health under award no. R35GM124736 (Rothbart). Scott Rothbart, Ph.D., was supported by an American Cancer Society Research Scholar Grant RSG-21-031-01-DMC (https://doi.org/10.53354/ACS.RSG-21-031-01-DMC.pc.gr.144230). Rochelle L. Tiedemann, Ph.D., was supported by the American Cancer Society–Michigan Cancer Research Fund Postdoctoral Fellowship (PF-16-245-01-DMC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funders.