KEAPing Tumor Cells Susceptible To Chemotherapy

Main Category: Lung Cancer
Article Date: 06 Oct 2006 - 7:00 PDT

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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.

Citation: Singh A, Misra V, Thimmulappa RK, Lee H, Ames S, et al.(2006) Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 3(10): e420.

PLEASE ADD THE LINK TO THE PUBLISHED ARTICLE IN ONLINE VERSIONS OF YOUR REPORT: http://dx.doi.org/10.1371/journal.pmed.0030420

Immunohistochemical staining of Nrf2 in NSCLC tumor tissue harboring KEAP1 mutation

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About PLoS Medicine

PLoS Medicine is an open access, freely available international medical journal. It publishes original research that enhances our understanding of human health and disease, together with commentary and analysis of important global health issues. For more information, visit http://www.plosmedicine.org/

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The Public Library of Science (PLoS) is a non-profit organization of scientists and physicians committed to making the world's scientific and medical literature a freely available public resource. For more information, visit http://www.plos.org/

CONTACT:

Shyam Biswal
Johns Hopkins University
Environmental Health Sciences
E7624, Hygiene
615N Wolfe Street
Baltimore, Maryland 21218u
United States of America

Contact: Sarah Clark
Public Library of Science

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