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Resistance to chemotherapy in lung cancer, optimizing flu vaccination strategies
October 03, 2006KEAPing tumor cells susceptible to chemotherapy
Lung cancer is the most common cause of cancer-related death worldwide, in part because these tumors often are or become resistant to chemotherapy. A study by Shyam Biswal and colleagues, published in the international open-access journal PLoS Medicine, now shines some light on what causes this resistance.
Cancer cells acquire resistance by making high levels of proteins that destroy chemotherapeutic agents (detoxification enzymes) or pump them out of cells (efflux pumps), and by making antioxidants that protect cells against the oxidative damage caused by some chemotherapy drugs. All of those proteins have normal functions as well; they protect cells from environmental toxins and from oxidants produced by the chemical processes of life.
Their production is regulated by NRF2, a transcription factor (a protein that controls the expression of other proteins) that is in turn controlled by a protein called KEAP1. Biswal and colleagues investigated whether changes in KEAP1 might underlie the drug resistance seen in many lung cancers. The researchers examined the KEAP1 gene in tissue taken from lung tumors and in several lung cancer cell lines and found mutations in KEAP1 in half the cell lines and a fifth of the tumor samples. They also found that about half of the samples had lost one copy of the KEAP1 gene-cells usually have two copies of each gene. Five of the six tumors with KEAP1 mutations had lost the other (functional) copy of KEAP1-geneticists call this biallelic inactivation-leaving them without any functional KEAP1.
As would be expected, the tumor cells had more NRF2 than normal cells and also made more detoxification enzymes, efflux proteins, and antioxidants than normal cells. And Biswal and colleagues showed that lung cancer cells with KEAP1 mutations were more resistant to chemotherapy drugs than normal lung cells.
These results indicate that biallelic inactivation of KEAP1 is a frequent genetic alteration in lung cancer and suggest that the loss of KEAP1 activity is one way that lung tumors can increase their NRF2 activity and develop resistance to chemotherapeutic drugs. If other studies confirm that high NRF2 activity is associated with a poor response to chemotherapy, then the development of NRF2 inhibitors might help to improve treatment outcomes in patients with chemotherapy-resistant tumors.
Public Library of Science
Their production is regulated by NRF2, a transcription factor (a protein that controls the expression of other proteins) that is in turn controlled by a protein called KEAP1. Biswal and colleagues investigated whether changes in KEAP1 might underlie the drug resistance seen in many lung cancers. The researchers examined the KEAP1 gene in tissue taken from lung tumors and in several lung cancer cell lines and found mutations in KEAP1 in half the cell lines and a fifth of the tumor samples. They also found that about half of the samples had lost one copy of the KEAP1 gene-cells usually have two copies of each gene. Five of the six tumors with KEAP1 mutations had lost the other (functional) copy of KEAP1-geneticists call this biallelic inactivation-leaving them without any functional KEAP1.
As would be expected, the tumor cells had more NRF2 than normal cells and also made more detoxification enzymes, efflux proteins, and antioxidants than normal cells. And Biswal and colleagues showed that lung cancer cells with KEAP1 mutations were more resistant to chemotherapy drugs than normal lung cells.
These results indicate that biallelic inactivation of KEAP1 is a frequent genetic alteration in lung cancer and suggest that the loss of KEAP1 activity is one way that lung tumors can increase their NRF2 activity and develop resistance to chemotherapeutic drugs. If other studies confirm that high NRF2 activity is associated with a poor response to chemotherapy, then the development of NRF2 inhibitors might help to improve treatment outcomes in patients with chemotherapy-resistant tumors.
Public Library of Science
Chemotherapy Current Events and Chemotherapy News RSSNew cancer target for non-Hodgkin's lymphoma
Physician-scientists from Weill Cornell Medical College have discovered a molecular mechanism that may prove to be a powerful target for the treatment of non-Hodgkin's lymphoma, a type of cancer that affects lymphocytes, or white blood cells.
Fertility procedures need not delay breast cancer treatment for younger women
A new study published in the November issue of the Journal of the American College of Surgeons shows that breast cancer patients under 40 years old who undergo fertility preservation do not face a significant delay in the treatment of their disease when their care is coordinated in a timely fashion.
Drugs to treat anemia in cancer patients linked to thromboembolism
Medications frequently given to cancer patients to reduce their risk of anemia are associated with an increased risk of deep vein thrombosis or pulmonary embolism, according to new research led by Dawn Hershman, M.D, M.S., co-director of the breast cancer program at the Herbert Irving Comprehensive Cancer Center at NewYork-Presbyterian Hospital/Columbia University Medical Center.
For young boys with cancer, testicular tissue banking may be option to preserve fertility
For parents of children with cancer, the hopeful news is that pediatric survival rates have steadily improved for decades. Among the bad news-treatments that enable survival often cause infertility.
FDA approved leukemia drugs shows promise in ovarian cancer cells
The drug Sprycel, approved for use by the U.S. Food and Drug Administration in patients with chronic myeloid leukemia, significantly inhibited the growth and invasiveness of ovarian cancer cells and also promoted their death, a study by researchers with UCLA's Jonsson Comprehensive Cancer Center found.
1930s drug slows tumor growth
Drugs sometimes have beneficial side effects. A glaucoma treatment causes luscious eyelashes. A blood pressure drug also aids those with a rare genetic disease.
First use of antibody and stem cell transplantation to successfully treat advanced leukemia
For the first time, researchers at Fred Hutchinson Cancer Research Center have reported the use of a radiolabeled antibody to deliver targeted doses of radiation, followed by a stem cell transplant, to successfully treat a group of leukemia and pre-leukemia patients for whom there previously had been no other curative treatment options.
New Synthetic Molecules Trigger Immune Response to HIV and Prostate Cancer
Researchers at Yale University have developed synthetic molecules capable of enhancing the body's immune response to HIV and HIV-infected cells, as well as to prostate cancer cells. Their findings, published online in the Journal of the American Chemical Society, could lead to novel therapeutic approaches for these diseases.
Chemo-radiation before prostate removal may prevent cancer recurrence
Researchers in the Oregon Health & Science University Knight Cancer Institute and the Portland Veterans Affairs Medical Center have found a combination of radiation therapy and chemotherapy given before prostate removal is safe and may have the potential to reduce cancer recurrence and improve patient survival.
PMH finding may help some tonsil cancer patients avoid chemotherapy
Clinical researchers at Princess Margaret Hospital (PMH) have confirmed that patients with oropharyngeal squamous cell cancer ("tonsil cancer") harbour a common type of human papilloma virus (HPV16), but also that such cancers are very sensitive to radiation.
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