Power of cancer drugs may see boost by targeting newly ID'd pathway

Cells zealously protect the integrity of their genomes, because damage can lead to cancer or cell death. The genome - a cell's complete set of DNA - is most vulnerable while it is being duplicated before a cell divides. Cancer cells constantly are dividing, so their genomes are constantly in jeopardy.

Researchers at Washington University School of Medicine in St. Louis have identified a previously unknown signaling pathway cells use to protect their DNA while it is being copied. The findings, published Jan. 24 in the journal Molecular Cell, suggest that targeting this pathway potentially could boost the potency of cancer therapeutics.

"A cell that can't protect its genome is going to die," said senior author Zhongsheng You, PhD, a professor of cell biology & physiology. "This entire pathway we found exists to protect the genome so the cell can survive in the face of replication stress. By combining inhibitors of this pathway with chemotherapy drugs that target the DNA replication process, we potentially could make such drugs more effective."

Replication stress occurs when the cell’s DNA duplication machinery runs into problems copying the genome. Certain stretches of DNA are inherently difficult to copy, because they contain many repeated sequences. Factors that damage the DNA, such as radiation and toxic molecules, also cause replication stress, as does the activation of cancer-causing genes. Dozens of cancer drugs, including widely used medications such as cisplatin and doxorubicin, work by damaging the DNA and increasing replication stress.

You studies how cells protect their genomes while they are being duplicated. Early in his career, he worked on the ATR-Chk1 genome-protection pathway - a pathway that controls the cell-division cycle and prevents stalled replication machinery from failing entirely and causing breaks in the DNA. For the past eight years, he and his team painstakingly have been piecing together another previously unknown genome-protection pathway. With this new study, the final piece of the puzzle has clicked into place.

The process they discovered goes like this: When the DNA-duplicating machinery stalls, a protein called Exo1 that normally follows behind the machinery gets a little out of hand. Exo1’s job is to perform quality control by cutting out incorrectly copied pieces of DNA, but when the machinery stops moving forward, Exo1 starts snipping away haphazardly, cleaving off bits of DNA that then make their way out of the nucleus and into the main part of the cell. DNA is not found outside the nucleus under normal conditions, so its presence in the main part of the cell sets off an alarm. Upon encountering a fragment of DNA, a sensor molecule triggers a cascade of molecular events, including the release of the calcium ion from a cellular organelle known as the endoplasmic reticulum, which in turn shuts down Exo1, preventing it from dicing up the genome any further until the problem with the machinery can be fixed.

This newest study describes the discovery of DNA fragments as the warning signal that sets off the whole genome-protection response. The study was led by first author Shan Li, PhD, as a postdoctoral researcher and then a staff scientist in You’s lab. Li is now an assistant professor at Zhejiang University School of Medicine in Hangzhou, China. Co-author Lingzhen Kong, a graduate student, also made important contributions to the study.

Over the years, You and colleagues have identified eight protein factors involved in this genome-protection pathway. Most of them already have inhibitors under development that could be repurposed for cancer studies.

"Now that we have the pathway, we want to know whether it can be targeted for cancer treatment," You said. "Lung, ovarian and breast cancer are intrinsically under replication stress. Other cancers are put under replication stress by chemotherapy drugs. This pathway protects cells from replication stress, so if we could block the pathway, it might improve patients’ response to cancer therapies."

Several of the proteins in this pathway also play a role in other critical biological processes, including immunity, metabolism and autophagy, the process by which cells break down their own unwanted materials.

"One of the most exciting things about this pathway is how it intersects with so many other pathways," You said. "I've been focusing on cancer, but much of this could also apply to autoimmune diseases. Two of the proteins we identified have been linked to chronic activation of the immune response and autoimmune disease. We want to understand the relationship between this replication-stress response pathway and the innate immune response pathway. The work we do is very basic, and it is so exciting to connect the dots between these fundamental processes and see how they relate to human health and disease."

Shan Li, Lingzhen Kong, Ying Meng, Chen Cheng, Delphine Sangotokun Lemacon, Zheng Yang, Ke Tan, Abigael Cheruiyot, Zhimin Lu, Zhongsheng You.
Cytosolic DNA sensing by cGAS/STING promotes TRPV2-mediated Ca2+ release to protect stressed replication forks.
Molecular Cell, 2023. doi: 10.1016/j.molcel.2022.12.034

Most Popular Now

AstraZeneca to acquire CinCor Pharma to strengthen…

AstraZeneca has entered into a definitive agreement to acquire CinCor Pharma, Inc. (CinCor), a US-based clinical-stage biopharmaceutical company, focused on developing no...

NextPoint Therapeutics announces $80 million Serie…

NextPoint Therapeutics, a biotechnology company developing a new world of precision immuno-oncology, announced today that it raised $80 million in Series B financing co-l...

Time-restricted eating reshapes gene expression th…

Numerous studies have shown health benefits of time-restricted eating including increase in life span in laboratory studies, making practices like intermittent fasting a ...

Incurable liver disease may prove curable

Research led by Associate Professor Duc Dong, Ph.D., has shown for the first time that the effects of Alagille syndrome, an incurable genetic disorder that affects the li...

Scientists develop a cancer vaccine to simultaneou…

Scientists are harnessing a new way to turn cancer cells into potent, anti-cancer agents. In the latest work from the lab of Khalid Shah, MS, PhD, at Brigham and Women’s ...

Bayer to accelerate drug discovery with Google Clo…

Bayer AG and Google Cloud announced a collaboration to drive early drug discovery that will apply Google Cloud's Tensor Processing Units (TPUs), which are custom-develope...

COVID-19 vaccines, prior infection reduce transmis…

Vaccination and boosting, especially when recent, helped to limit the spread of COVID-19 in California prisons during the first Omicron wave, according to an analysis by ...

Study identifies potential new approach for treati…

Targeting iron metabolism in immune system cells may offer a new approach for treating systemic lupus erythematosus (SLE) - the most common form of the chronic autoimmune...

Nanotechnology may improve gene therapy for blindn…

Using nanotechnology that enabled mRNA-based COVID-19 vaccines, a new approach to gene therapy may improve how physicians treat inherited forms of blindness. A collabo...

Acquisition of Neogene Therapeutics completed

AstraZeneca has completed the acquisition of Neogene Therapeutics Inc. (Neogene), a global clinical-stage biotechnology company pioneering the discovery, development and ...

Modified CRISPR-based enzymes improve the prospect…

Many genetic diseases are caused by diverse mutations spread across an entire gene, and designing genome editing approaches for each patient’s mutation would be impractic...

Pfizer expands 'An Accord for a Healthier World' p…

Pfizer Inc. (NYSE: PFE) announced that it has significantly expanded its commitment to An Accord for a Healthier World to offer the full portfolio of medicines and vaccin...