Why some cancers may respond poorly to key drugs discovered

September 22, 2020

Patients with BRCA1/2 mutations are at higher risk for breast, ovarian and prostate cancers that can be aggressive when they develop - and, in many cases, resistant to lifesaving drugs. Now scientists at The University of Texas at Austin and Ajou University in South Korea have identified a driver of the drug resistance that can make a life or death difference for patients with these cancers.

"A major issue with cancer treatments is the development of resistance," said Kyle Miller, a UT Austin associate professor of molecular biosciences. "When treatments stop working for patients, it's incredibly demoralizing and it's been a huge drive in research to understand these resistance mechanisms."

In a paper published today in the journal Molecular Cell, the researchers describe a protein that may help doctors predict which patients will become resistant to a class of drugs frequently used to treat BRCA 1/2-deficient tumors. The finding could help create more effective treatment plans for their patients.

The scientists identified that a protein called PCAF promotes DNA damage in BRCA 1/2-mutated cancer cells. Patients with low levels of this protein are likely to have poor outcomes and develop resistance to a type of drug that is used to treat BRCA-deficient tumors, called a PARP inhibitor.

"PARP inhibitors are an important breakthrough in treating these aggressive cancers," Miller said. "What we found is that when levels of PCAF are low, it actually protects the cancer cells from this drug. By testing biopsy samples, doctors may be able to tell using PCAF as a molecular marker for PARP inhibitor responses what treatment may work best for a patient."

Fortunately, there is already another class of drugs on the market, called HDAC inhibitors, that can boost the effectiveness of the PCAF protein. HDAC inhibitors and PARP inhibitors have the potential to be prescribed as a combination therapy.

"Previous studies have shown that these two drugs work well together," Miller said. "We believe we've found the reason why."

It is possible to test for PCAF levels in biopsy or tissue samples, Miller said, and in the future, the test could be included on a standard panel for cancer testing.

But unlocking the workings of PCAF doesn't just offer clues to combatting cancer. Because this protein is responsible for modifying chromatin, the stuff that organizes 6 feet of DNA in each of our cells so that it fits into its nuclear volume, PCAF also may offer important clues about cell replication.

"The focus in my lab is on understanding chromatin and its impact on replicating DNA, protecting DNA and controlling access to DNA," Miller said. "Our goal is to understand how every molecule is interacting inside our cells, as this gives clues to what is going wrong in human diseases."
-end-
Jae Jin Kim and Seo Yun Lee from the Miller lab were first authors on the paper, and Blerta Xhemalce, an associate professor of molecular biosciences at UT Austin, and Ji-Hye Choi and Hyun Goo Woo of Ajou University contributed to the research.

The research was funded by the National Cancer Institute, the National Institutes of Health, the American Cancer Society, the Department of Defense - Congressionally Directed Medical Research Program - Breast Cancer Breakthrough Award and the National Research Foundation of Korea. Miller is a CPRIT scholar with the Cancer Prevention & Research Institute of Texas, a member of the Livestrong Cancer Institutes of Dell Medical School and a member of the Dan Duncan Cancer Center at the Baylor College of Medicine.

University of Texas at Austin

Related Cancer Cells Articles from Brightsurf:

Cancer researchers train white blood cells to attacks tumor cells
Scientists at the National Center for Tumor Diseases Dresden (NCT/UCC) and Dresden University Medicine, together with an international team of researchers, were able to demonstrate that certain white blood cells, so-called neutrophil granulocytes, can potentially - after completing a special training program -- be utilized for the treatment of tumors.

New way to target some rapidly dividing cancer cells, leaving healthy cells unharmed
Scientists at Johns Hopkins Medicine and the University of Oxford say they have found a new way to kill some multiplying human breast cancer cells by selectively attacking the core of their cell division machinery.

Breast cancer cells use message-carrying vesicles to send oncogenic stimuli to normal cells
According to a Wistar study, breast cancer cells starved for oxygen send out messages that induce oncogenic changes in surrounding normal epithelial cells.

Breast cancer cells turn killer immune cells into allies
Researchers at Johns Hopkins University School of Medicine have discovered that breast cancer cells can alter the function of immune cells known as Natural killer (NK) cells so that instead of killing the cancer cells, they facilitate their spread to other parts of the body.

Breast cancer cells can reprogram immune cells to assist in metastasis
Johns Hopkins Kimmel Cancer Center investigators report they have uncovered a new mechanism by which invasive breast cancer cells evade the immune system to metastasize, or spread, to other areas of the body.

Engineered immune cells recognize, attack human and mouse solid-tumor cancer cells
CAR-T therapy has been used successfully in patients with blood cancers such as lymphoma and leukemia.

Drug that keeps surface receptors on cancer cells makes them more visible to immune cells
A drug that is already clinically available for the treatment of nausea and psychosis, called prochlorperazine (PCZ), inhibits the internalization of receptors on the surface of tumor cells, thereby increasing the ability of anticancer antibodies to bind to the receptors and mount more effective immune responses.

Engineered bone marrow cells slow growth of prostate and pancreatic cancer cells
In experiments with mice, researchers at the Johns Hopkins Kimmel Cancer Center say they have slowed the growth of transplanted human prostate and pancreatic cancer cells by introducing bone marrow cells with a specific gene deletion to induce a novel immune response.

First phase i clinical trial of CRISPR-edited cells for cancer shows cells safe and durable
Following the first US test of CRISPR gene editing in patients with advanced cancer, researchers report these patients experienced no negative side effects and that the engineered T cells persisted in their bodies -- for months.

Zika virus' key into brain cells ID'd, leveraged to block infection and kill cancer cells
Two different UC San Diego research teams identified the same molecule -- αvβ5 integrin -- as Zika virus' key to brain cell entry.

Read More: Cancer Cells News and Cancer Cells Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.