Scientists discover a mechanism of drug resistance in breast and ovarian cancer

July 18, 2018, Rockefeller University
By preventing DNA repair, PARP inhibitor drugs cause cancer cells to accumulate mutated chromosomes, ultimately killing them. Credit: Laboratory of Cell Biology and Genetics at The Rockefeller University

There is a highly sophisticated way to treat some breast and ovarian cancers—a class of drugs called PARP inhibitors, designed to exploit the very defects that make tumors with certain mutations especially deadly. Yet this targeted approach to cancer therapy sometimes fails, and scientists have anxiously sought to understand why.

Now, research at The Rockefeller University offers insight into the biology behind this and fresh hope for fighting it. Scientists in Titia de Lange's lab and their colleagues have discovered the molecular means by which some cancers caused by errors in the gene BRCA1 evade treatment by drugs custom-tailored to kill them.

Described in Nature on July 18, their work challenges previous assumptions about the mechanics by which these PARP inhibitors succeed or fail to help patients.

"This is a complete shift in our understanding of the mechanism that underlies this form of treatment for BRCA1 cancers," says de Lange, the Leon Hess Professor.

Their discovery helps to explain why some cancers respond to PARP inhibitors, while others do not—an insight that could ultimately be used to help improve treatments for patients.

A defect—and an opportunity

Experts predict that about 288,000 new cases of breast and ovarian will be diagnosed this year. A substantial fraction of these cancers are caused by harmful errors in two of the most infamous constituents of the human genome: the genes known as BRCA1 and BRCA2. Mutations in BRCA1—the subject of the new research—have been estimated to give a woman a roughly 72 percent chance of developing breast cancer and a 44 percent chance of developing ovarian cancer by the age of 80.

Both genes are tumor suppressors, meaning they normally help keep the body cancer-free. They code for proteins that are important for properly repairing a DNA molecule that has been cut somewhere along its length—a mishap called a double-strand break, since it severs both strands of the DNA helix. Without the BRCA genes, the broken DNA isn't fixed properly, producing mutations that can lead to cancer.

In recent years, the development of new drugs called PARP inhibitors made it possible to turn those same genetic defects against the disease. The drugs prompt the formation of double-strand breaks; unable to properly repair these breaks, BRCA-deficient tumor cells die.

However, some tumors that should be vulnerable to PARP inhibitors don't respond. Scientists think this failure occurs for a number of reasons, and researchers in de Lange's lab homed in on one culprit linked to resistance in BRCA1 cancers in particular.

For nearly a decade, scientists had known that the loss of a protein called 53BP1 made it possible for BRCA1-deficient cells to overcome their inherent defect and properly repair double-strand breaks. This type of resistance can emerge during or after PARP inhibitor treatment when some tumor cells thrive after mutating to lose 53BP1. But it wasn't clear why losing this protein gives these cancer cells such a deadly advantage.

A different mechanism

In order to prepare a broken DNA molecule for repair, one strand of the broken double-helix first needs to be trimmed back. It was assumed that 53BP1 prevents this pruning. Lose 53BP1, the thinking went, and BRCA1-deficient cells suddenly gain the ability to repair their DNA breaks.

In experiments, de Lange's team showed that 53BP1 does something different. Work by Zachary Mirman, a graduate student in the lab; Francisca Lottersberger, a former postdoc; and their colleagues found that 53BP1 instead helps to counteract the pruning process by rewriting sections of DNA cut from these loose strands.

In BRCA1-deficient cancers treated with PARP inhibitors, the rewriting function of 53BP1 leads to faulty repair of DNA and the death of the cancerous cells. Yet some of these cells manage to escape treatment by losing 53BP1. The work from de Lange's lab explains just how this change allows them to survive.

"In the big picture, this new insight into 53BP1's function and its role in drug resistance provides a foundation for advancements in PARP inhibitor therapy," Mirman says. These improvements could include the development of screening tests to see which tumors would best respond to PARP inhibitors, or to determine which other drugs should—or should not—be given along with them, the researchers say.

Explore further: Researchers suggest new treatment for rare inherited cancers

More information: Zachary Mirman et al, 53BP1–RIF1–shieldin counteracts DSB resection through CST- and Polα-dependent fill-in, Nature (2018). DOI: 10.1038/s41586-018-0324-7

Related Stories

Researchers suggest new treatment for rare inherited cancers

July 16, 2018
Studying two rare inherited cancer syndromes, Yale Cancer Center (YCC) scientists have found the cancers are driven by a breakdown in how cells repair their DNA. The discovery, published today in Nature Genetics, suggests ...

Novel combination therapy shown to be effective in ovarian cancer

December 19, 2017
Researchers at The Wistar Institute have found that combining PARP inhibitors, recently approved for the treatment of BRCA-mutant ovarian cancer, with another small molecule inhibitor was effective to treat ovarian cancers ...

'Cell' article reveals new resistance mechanism to chemotherapy in breast and ovarian cancer

June 18, 2013
It is estimated that between 5% and 10% of breast and ovarian cancers are familial in origin, which is to say that these tumours are attributable to inherited mutations from the parents in genes such as BRCA1 or BRCA2. In ...

Scientists identify cause of resistance to breakthrough breast and ovarian cancer drug

May 10, 2018
Scientists have identified a mutation that gives cancer cells resistance to the breakthrough cancer treatment olaparib and other PARP inhibitors.

New findings may enhance PARP inhibitors therapy in breast cancer

January 18, 2016
Findings from a new study reveal that PARP inhibitors, an emerging class of drugs being studied in cancer clinical trials, may be enhanced by combining them with inhibitors targeting an oncogene known as c-MET which is overexpressed ...

Recommended for you

Brigatinib becomes potential new first-line option for ALK-positive non-small lung cancer

September 25, 2018
Results of a 275-patient, multi-national phase III clinical trial known as ALTA-1L published today in the New England Journal of Medicine and presented concurrently in the press program at the International Association for ...

A protein called vaccinia-related kinase 1 may help cancer establish itself in new areas of the body during metastasis

September 25, 2018
Sometimes negative results can point researchers in the right direction.

Two studies describe improved approach to bone marrow transplant

September 25, 2018
Two recent studies in the journal Leukemia present a new approach for bone marrow donation and transplant that preclinical laboratory tests suggest could make the life-saving procedure safer and more effective for patients.

Combo therapy of prostatectomy plus radiotherapy may improve survival in prostate cancer

September 25, 2018
High-risk prostate cancer, that which has continued to grow but not yet metastasized, is commonly treated with combination therapies. Each method has pros and cons, but there is little clarity whether one might be more effective ...

Method identified to reduce risk of brain damage in leukemia survivors

September 25, 2018
Children with acute lymphoblastic leukemia (ALL) are at an extremely high risk of sepsis compared to the general population. In the first-published study of its kind, St. Jude Children's Research Hospital scientists have ...

Unhealthy lifestyle responsible for 45,000 predicted cases of bowel cancer in next decade

September 25, 2018
A UNSW study shows that a large proportion of bowel cancers in Australia are preventable by adopting a healthy lifestyle – particularly for men.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.