It’s a typical objective in cancer research to identify something in cancer cells – some sort of chemical – that drives their capacity to survive, and then see whether that molecule can be blocked by a medication, halting tumor development. Even better, because the chemical isn’t present in healthy cells, the new treatment does not affect them.
RNA-Binding Proteins Might Be A Promising Therapeutic Target To Treat Breast Cancer
This method, known as molecular targeted cancer treatment, has made significant progress. Some modern cancer therapies block hyperactive enzymes, allowing cells to grow, disseminate, and survive beyond their normal limits. The problem is that many recognized cancer-causing molecules are undruggable, which means that medicines cannot attach to them due to their type, shape, or location.
Researchers at the University of California San Diego School of Medicine are currently investigating the therapeutic potential of RNA-binding proteins, a largely unknown class of cancer-causing chemicals. Following the transcription of genes (DNA) into RNA, these proteins provide an additional layer of cellular control by selecting which RNA copies are translated into other proteins and which are not. When RNA-binding proteins fail, they, like many other molecular mechanisms that regulate cell proliferation, can contribute to tumor formation.
The UC San Diego School of Medicine researchers found in human cells and mouse models that RNA-binding proteins represent a new class of drug targets for cancers, including triple-negative breast cancer, a particularly difficult-to-treat cancer because it lacks most other molecular drug targets, in their latest study, which will be published on July 2, 2021, in Molecular Cell.
YTHDF2 was one RNA-binding protein that stood out in particular. When the researchers eliminated YTHDF2 from human triple-negative breast cancers implanted into mice, the tumors shrunk by around tenfold.
They are enthusiastic because RNA-binding proteins appear to represent a new class of cancer therapeutic targets, according to lead author Gene Yeo, Ph.D., professor of cellular and molecular medicine at UC San Diego School of Medicine. They are unsure how easily druggable they are in this setting, but they have established a strong foundation to begin investigating them.
The work was co-led by Yeo and Jaclyn Einstein, Ph.D., a graduate student in his group. Einstein will join a startup firm created out of the lab to investigate the druggability of YTHDF2.
Yeo’s team has long been interested in the role of RNA-binding proteins in a variety of different illnesses. They found, for example, in 2016 that mutations in one of these proteins lead to ALS by disrupting critical cellular communications networks.
The researchers used an ancient idea known as synthetic lethality to begin investigating RNA-binding proteins as cancer treatment targets. They began with human breast cells modified to over-produce another well-known cancer-driving protein and then sought for other vulnerabilities particular to those cells in this one-two punch strategy.
Using the CRISPR gene editing method, the researchers suppressed RNA-binding proteins in these cancer cells one by one. They discovered 57 RNA-binding proteins that, when blocked, kill cancer cells driven by a known hyperactive cancer driver. The benefit of the synthetic lethal method is that normal cells, which do not generate the cancer-causing chemical, should be unaffected by the treatment. YTHDF2 was the most promising of these 57 RNA-binding proteins.
Yeo’s group has also recently developed a novel laboratory approach known as Surveying Targets by APOBEC-Mediated Profiling (STAMP), which allows them to assess what was previously completely invisible: how RNA-binding proteins interact with RNA molecules within individual cells.
In this work, the researchers utilized STAMP to obtain a comprehensive look at how the different cells that make up a breast tumor behave without YTHDF2. The method indicated that YTHDF2-deficient cancer cells die as a result of stress-induced apoptosis, a tightly regulated mechanism by which cells kill themselves. Apoptosis is meant to kill faulty cells and prevent tumors from forming, but it doesn’t always succeed. They were able to reactivate this cell death signal by deleting YTHDF2