Potential target of difficult-to-treat breast cancer drugs: RNA-binding proteins

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Negative triple breast cancer cells are shown on the left. Without the YTHDF2 RNA-binding protein (right), fewer cancer cells survived. Credit: UC San Diego Health Sciences

In cancer research, it is a common goal to find something about cancer cells (some type of molecule) that boosts their ability to survive and determine if that molecule could be inhibited with a drug, stopping tumor growth. Even better: the molecule is not present in healthy cells, so they remain intact with the new therapy.

Much progress has been made in this approach, known as the molecular goal . Some current cancer therapies inhibit enzymes that become hyperactive, allowing proliferate, spread and survive beyond its norm. The challenge is that many known molecules that drive cancer are “indestructible,” meaning their type, shape, or location prohibits drugs from binding to them.

Researchers at the University of California San Diego School of Medicine are now exploring the therapeutic potential of RNA-binding proteins, a family of molecules that drive cancer relatively unexploited. After transcribing the genes (DNA) into RNA, these proteins provide an additional layer of cell control, determining which copies of RNA are translated into other proteins and which are not. Like many who govern RNA-binding proteins can contribute to tumor development when they malfunction.

In his latest study, published on July 2, 2021 a Molecular cell, the medical team at UC San Diego School of Medicine discovered in and mouse models that RNA-binding proteins represent a new class of pharmacological targets for cancer, including , a cancer that is especially difficult to treat because it does not have most other molecular targets.

In particular, he highlighted an RNA-binding protein: YTHDF2. When the researchers genetically removed YTHDF2 from triple-negative human breast tumors transplanted into mice, the tumors were reduced by approximately ten times their volume.

“We’re excited that RNA-binding proteins look like they could be a new class of pharmacological targets for cancer,” said lead author Gene Yeo, Ph.D., professor of medicine cellular and molecular at UC San Diego School of Medicine. “We’re still not sure how easily they are drugged in this context, but we’ve built a solid framework to start exploring them.”

Yeo led the study with Jaclyn Einstein, Ph.D., a graduate student in her lab. Einstein will join a start-up company that left the lab to explore the possibility of acquiring YTHDF2.

Yeo’s team has long studied the role of RNA-binding proteins in other diseases. In 2016, for example, they discovered that there were mutations in one of these proteins contribute to ALS mixing crucial cellular messaging systems.

To begin exploring RNA-binding proteins as anti-cancer targets, researchers resorted to an old philosophy known as synthetic lethality. In this two-pronged approach, they started with human breast cells designed to overproduce another known molecule that leads to cancer and looked for additional vulnerabilities specific to those cells.

The researchers systematically silenced RNA-binding proteins one by one using the CRISPR gene editing technique. They found 57 RNA-binding proteins that, when inhibited, kill cancer cells with the well-known hyperactive cancer factor. The advantage of the synthetic lethal approach is that , which do not produce this molecule that leads to cancer, should be left intact by treatment. Of these 57 RNA-binding proteins, YTHDF2 looked more promising.

Yeo’s team too newly developed a new laboratory technique called Surveying Targets by APOBEC-Mediated Profiling (STAMP), which allows them to measure what was previously largely invisible: how RNA-binding proteins interact with RNA molecules within cells · Individual cells.

The researchers used STAMP in this study to get a detailed view of how the various cells that make up a breast tumor without YTHDF2 behave. The approach revealed that YTHDF2-deficient cancer cells die from stress-induced apoptosis, a carefully controlled mechanism that cells use to destroy themselves. Apoptosis is supposed to close cells that do not work so that tumors do not arise, but it does not always work. By removing YTHDF2, they were able to reactivate this cell death signal.

To test for the risk of treating cancer by inhibiting YTHDF2, researchers have designed mice that lack YTHDF2 in all cells in the adult body, not just transplanted breast cancer cells. Mice looked completely normal, not only did they have no tumors, there were no changes in body weight or behavior.

“These healthy mice tell us that we could expect minimal adverse side effects from potential therapies that work by targeting YTHDF2,” Einstein said.


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More information:
Molecular cell (2021). DOI: 10.1016 / j.molcel.2021.06.014 , www.cell.com/molecular-cell/fu … 1097-2765 (21) 00493-7

Citation: Potential pharmacological target for difficult-to-treat breast cancer: RNA-binding proteins (2021, July 2) recovered on July 3, 2021 at https://medicalxpress.com/news/2021- 07-potential-drug-difficult-to-treat-breast-cancer.html

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