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A long-standing mystery in cancer treatment is how tumor cells so often become resistant to drugs, even ones they have never encountered before.

Researchers at 91��Ƭ�� Langone Health propose a model that could explain how cancer cells adapt to environmental stress, an approach that may lead to new therapies.

Published online April 15 as the cover story of the journal Nature, the perspective article centers on a family of proteins called AP-1, which are quickly activated in cells in response to stressful situations—like being exposed to chemotherapy.

While AP-1 proteins have been studied for many decades, the authors propose they are part of a previously overlooked molecular mechanism in which cells survive by learning to rewire their circuitry. This process depends not on permanent changes to a cell’s DNA code, but rather on the cell’s ability to turn genes on or off, and then “remember” the changes that improve its survival chances.

The work suggests that cancer cells use this plasticity to explore gene expression patterns until they find a combination that helps them survive. Once a successful survival state is discovered, it can be locked in and passed down to future cell generations, leading to drug-resistant tumors.

“For decades, our understanding of drug resistance was that it was primarily caused by the selection of rarely occurring genetic mutations—or changes in the DNA code—that happen to be effective against a specific drug,” said study author , a professor in the at 91��Ƭ�� Langone.

“More recently, we’ve learned that cells can change cellular states to adapt to treatments, but the mechanism has not been clear,” added Dr. Yanai, who is a faculty member of the . “We propose the existence of a surprising mechanism whereby cells adapt on the fly, and which may explain why advanced cancers become virtually untreatable.”

“Our AP-1 model works like an evolutionary algorithm inside each cancer cell,” said first author Gustavo S. França, PhD, a postdoctoral fellow in Dr. Yanai’s lab. “By deploying AP-1, the cell is able to generate different ways to regulate its genes and then select the one that is most adaptive to its environment.”

Mix and Match

Dr. Yanai and Dr. França’s proposed mechanism involves transcription factors, proteins that bind to DNA and control the activity of hundreds of genes. The AP-1 family is unique because its member proteins can pair up with each other in many combinations, or “dimers,” each regulating a different gene set in a particular cellular context.

According to the framework, this combinatorial flexibility acts as a survival tool kit for cancer cells, letting them explore different gene expression patterns to test which one best helps them withstand the stress caused by the cancer drug. The researchers hypothesize that a feedback loop exists in which AP-1 dimers that successfully reduce the cellular stress are stabilized, while ineffective ones are discarded.

Over time, the cells arrive at an optimal AP-1 combination that alters their genome regulation in ways that enables them to survive. These epigenetic changes then serve as a form of cellular memory, ensuring the newly acquired resistant state is passed down to the next generation of cells.

“Our new model could have profound implications for how we think about treating cancer,” said Dr. Yanai. “Instead of targeting its particular state, as most current therapies do, we may also need to target its ability to adapt. If we can block this AP-1 learning mechanism, we may be able to prevent cancer cells from ever becoming treatment resistant in the first place.”

The study authors noted that this mechanism of cellular adaptation may have implications beyond cancer. Evidence suggests that similar AP-1-mediated processes are at play in normal biological functions, such as memory formation in the brain and wound healing in the skin.

Looking ahead, the team plans to use advanced technologies, such as CRISPR gene editing and single-cell analysis, to systematically map the different AP-1 combinations and determine how each one contributes to drug resistance.

“Our next step is to dissect the AP-1 phosphorylation code,” said Dr. França. “By understanding precisely which AP-1 pairs drive resistance to specific therapies, we can begin to combine conventional cancer therapies with anti-adaptation agents to create treatments that are effective for longer.”

This work was supported by National Institutes of Health grants R01CA296978, U01CA260432, R01LM013522, U54CA263001, and R21CA264361.

About 91��Ƭ�� Langone Health

91��Ƭ�� Langone Health is a fully integrated health system that consistently achieves the best patient outcomes through a rigorous focus on quality that has resulted in some of the lowest mortality rates in the nation. Vizient Inc. has ranked 91��Ƭ�� Langone No. 1 out of 118 comprehensive academic medical centers across the nation for four years in a row, and U.S. News & World Report recently ranked four of its clinical specialties No. 1 in the nation. 91��Ƭ�� Langone offers a comprehensive range of medical services with one high standard of care across seven inpatient locations, its Perlmutter Cancer Center, and more than 320 outpatient locations in the New York area and Florida. The system also includes two tuition-free medical schools, in Manhattan and on Long Island, and a vast research enterprise.

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