A long-standing mystery in cancer treatment is how tumor cells become resistant to drugs, even drugs they have never encountered before.
Researchers at New York University Langone Health have proposed a model that can explain how cancer cells adapt to environmental stress, an approach that could lead to new treatments.
Published online April 15 as a cover story for the journal naturethis Perspective focuses on a family of proteins called AP-1 that are rapidly activated within cells in response to stressful situations, such as exposure to chemotherapy.
Although the AP-1 protein has been studied for decades, the authors propose that it is part of a previously overlooked molecular mechanism by which cells survive by learning to rewire their circuits. Rather than making permanent changes to the cell’s DNA code, this process relies on the cell’s ability to “remember” changes that turn genes on or off, increasing the chances of survival.
This study suggests that cancer cells take advantage of this plasticity, exploring patterns of gene expression until they find a combination that helps them survive. Once a successful survival state is discovered, it can become trapped and passed on to future cell generations, giving rise to drug-resistant tumors.
For decades, our understanding of drug resistance has been that it is primarily caused by the selection of rare genetic mutations, or changes in the DNA code, that are more effective against certain drugs. ”
Dr. Itai Yanai, Study Author, Professor, Department of Chemistry and Molecular Pharmacology, New York University Langone College
“More recently, we have found that cells can change their state to adapt to treatments, but the mechanism is still unclear,” added Dr. Yanai, a faculty member at the Institute for Systems Genetics. “We propose the existence of a surprising mechanism by which cells adapt on the fly, which may explain why advanced cancers become virtually untreatable.”
“Our AP-1 model works like an evolutionary algorithm within each cancer cell,” said first author Dr. Gustavo S. França, a postdoctoral fellow in Dr. Yanai’s lab. “By deploying AP-1, cells can generate different ways to regulate genes and choose the one that best adapts to their environment.”
use in combination
The mechanism proposed by Yanai and França 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 pair up with each other in many combinations, or “dimers,” each of which can control a different set of genes in a particular cellular context.
According to this framework, this combinatorial flexibility serves as a survival toolkit for cancer cells, allowing them to explore different gene expression patterns and test which ones are most effective in withstanding stress caused by anticancer drugs. The researchers hypothesize that a feedback loop exists in which AP-1 dimers that are successful in reducing cellular stress are stabilized and ineffective AP-1 dimers are discarded.
Over time, cells reach an optimal AP-1 combination that alters genomic regulation in a way that allows survival. These epigenetic changes act as a form of cellular memory, ensuring that newly acquired resistant states are passed on to the next generation of cells.
“Our new model could have a significant impact on the way we think about cancer treatment,” Dr. Yanai said. “Rather than targeting that specific state, as most current treatments do, we may need to target that adaptive capacity. If we can block this AP-1 learning mechanism, we may be able to prevent cancer cells from becoming resistant to treatment in the first place.”
The study authors noted that this cellular adaptation mechanism may have implications beyond cancer. There is evidence that similar AP-1-mediated processes are at work 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 techniques such as CRISPR gene editing and single-cell analysis to systematically map different AP-1 combinations to understand how each contributes to drug resistance.
“Our next step is to analyze the phosphorylation code of AP-1,” said Dr. França. “By understanding precisely which AP-1 pairs cause resistance to a particular therapy, we will be able to combine traditional cancer treatments with anti-adaptive drugs to create longer-lasting treatments.”
This research was supported by National Institutes of Health grants R01CA296978, U01CA260432, R01LM013522, U54CA263001, and R21CA264361.
