Genetic Mutation That Makes Common Cancers Resistant to Drugs Identified

Researchers from Eli Lilly and Company and the Phoenix-based Translational Genomics Research Institute (TGen) have identified the genetic mutation that may alter tumour cell proliferation, and make them resistant to certain types of therapies.

The researchers say that they found a recurring mutation of the gene AKT1 in breast, colorectal, and ovarian cancers.

The AKT pathway is among the most commonly activated cellular pathways in human cancers and members of this pathway are among the most frequently targeted for new cancer drug discovery efforts.

The activation of this pathway results in cancer cell growth and cell survival, according to the background information in an article published in an advanced online publication of Nature magazine.

The researchers have for the first time found evidence of direct mutation of AKT1 in clinical samples of human cancer tumours.

"This discovery is a seminal finding in cancer biology that confirms AKT1 as an oncogene in breast, colorectal and ovarian cancer. The mutation alters the electrostatics of binding pocket in the pleckstrin homology domain, the portion of the enzyme that docks with phospholipids on the cell membrane," said Dr. Kerry L. Blanchard, Executive Director, Discovery Biology Research, Eli Lilly and Company.

During the study, the researchers analysed 150 tumour samples from patients with either breast, colorectal or ovarian cancer, and found that eight per cent of breast, six per cent of colorectal and two per cent of ovarian tumours had the AKT1 mutation.

"Recently, molecular features such as the AKT1 mutation are beginning to change drug development efforts. This discovery adds to the short but growing list of molecular features that may help guide both current and future cancer drug development," said Dr. John Carpten, Senior Investigator and Director of TGen's Integrated Cancer Genomics Division and the study's lead author.

"The next step is to determine the prevalence of the AKT1 mutation in different populations and, hopefully, use the information gained to stratify patients going into clinical trials for AKT inhibitors," he added.

The researchers say that their findings may help in the advancement of cancer treatment and drug development, if they are validated by further studies.

"This is a gorgeous study that used a variety of sophisticated techniques to provide new insights into the tumourigenic process," said Dr. Bert Vogelstein, Director of the Ludwig Center for Cancer Genetics and Therapeutics at The Johns Hopkins Kimmel Cancer Center.

Source-ANI
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