Locally adhered plaque kinase proteins are associated with chemotherapy resistance to ovarian cancer

Although the number of women diagnosed and dying from ovarian cancer is declining, relapses, drug resistance and mortality remain high for women with high levels of slurry ovarian cancer, the most common form of endothy ovarian cancer. In a new study published in the journal Doctor's Life, researchers at the University of California, San Diego School of Medicine linked changes in the protein-sticking plaque kinase (FAK) gene to cancer's ability to survive chemotherapy.
Dr. David D. Schlaepfer, a researcher and co-lead researcher at the Moores Cancer Center School of Medicine at the University of California, San Diego, and a professor in the Department of Obstetrics, Gynecology and Reproductive Sciences, said. "In the new tumor model, we are not expecting to link elevated levels of locally adhereted plaque kinases or gene amplification to the survival of cancer stem cells." We know that locally adhesive plaque kinases help tumors spread, but we were surprised to find that locally adhesive plaque kinases support DNA repair in the tumor's most important stem cell-like cells. This may be an important tool for tumors to resist platinum chemotherapy, which is the current standard of care. In
patients, ovarian tumors show high levels of locally adhesive plaque kinase, said Dr. Dwayne G. Stupack, associate professor of gynecology and co-lead researcher at Moores Cancer Center.
"There are a number of drugs that are being tested in early clinical trials, including at the University of California, San Diego Health Center, which inhibits locally adhesive plaque kinases," Stupack said. When we treated mice with chemically resistant tumors with chemical antibody inhibitors, they responded to chemotherapy. Mice that did not receive locally adhered spot kinase inhibitors were resistant. By understanding the biology behind this, it can help us prepare better combinations of drugs for clinical use. ROCKIF Trial: Carbitin-resistant ovarian cancer reactivated kinase inhibits locally adherent plaque kinase, led by Michael McHale M.D., professor of obstetrics and gynecology and reproductive sciences at the University of California, San Diego School of Medicine, and Dr. Michael McHale, M.D., who is working on a combination of the chemotherapy drug locally adhesive plaque kinase inhibitor defactinib and the chemotherapy drug carpentin and yew alcohol.“ If we can prevent recurrence, we could have huge benefits for patients," said McHale, co-author of the study.
The National Cancer Institute (NCI) estimates that 22,350 women will be diagnosed with ovarian cancer in 2019 and 13,980 will die. About one in 70 women will be diagnosed with the disease in their lifetime. Breast cancer is nine times more likely to develop cancer than ovarian cancer, but according to NCI, nearly 90 percent of women survive breast cancer for five years or more. More than half of women with ovarian cancer will die within five years of diagnosis.
Cure or mitigation depends on the elimination of all cancer cells, including micro-diseases. Before a formal diagnosis, ovarian cancer cells usually spread to other parts of the woman's body. Cells can grow into tiny lumps or larger balls, called tumor balls. Most patients develop ovarian cancer cells that develop into chemotherapy resistant.
The joint study, led by Schlaepfer and Stupack, focused on high-level slurry ovarian cancer, a subtype of epithelial cancer that starts on the outer surface of the ovaries or fallopian tubes. It accounts for about 52% of malignant ovarian cancer and the highest number of deaths.
The researchers compared ovarian cancer cells in mouse models in the early and late stages of the disease. Late invasive cells exhibit greater genetic changes that can grow into tumor spheres in laboratory dishes. One of the changes affected the genes that locally adhere to the plaque kinase, and it was found that the locally adhered plaque kinase gene replicated more than normal.
Locally adhered plaque kinase protein is an enzyme that helps cancer cells move. In cells in mice with advanced cancer, locally adhered plaque kinases are overactive and present at high levels. When authorities were growing as tumor spheres, tumors with excessive local adhesion to plaque kinases were more resistant to chemotherapy than early tumors. In patients undergoing chemotherapy, the team found that surviving tumor cells also showed high levels of locally adhesive plaque kinase activity.
To understand how locally glued plaque kinases make ovarian cancer cells resistant to chemotherapy, the researchers used gene editing to remove the locally glued plaque kinase gene. They found that without locally adhered plaque kinases, cells lacked a set of detoxifying enzymes and cells that repaired damaged DNA.
“ Patients with ovarian cancer usually respond well to first-line treatment, but in most cases the cancer relapses," Schlaepfer said.
"We know that stem cell-like cancer cell subpopents can survive chemotherapy and lead to relapse, drug resistance and even death," Schlaepfer said. These results suggest that locally adhered plaque kinase is a potentially important therapeutic weakness for tumor recurrence. ”（cyy123.com）