Genetic mutation that may alter response to cancer therapeutics found

Jul 4 2007

Researchers from Eli Lilly & Company and the Phoenix-based Translational Genomics Research Institute (TGen) today announced finding a novel recurring mutation of the gene AKT1 in breast, colorectal and ovarian cancers.

The altered form of AKT1 appears to cause tumor cell proliferation and may play a role in making cells resistant to certain types of therapies. The findings are reported in an advance online publication (AOP) of the journal Nature.

The PI3-Kinase/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. Activation of this pathway results in cancer cell growth and cell survival. Although AKT1 is central to pathway activation, its role in cancer has been that of an intermediary between mutated upstream regulatory proteins and downstream survival signaling proteins. This is the first evidence of direct mutation of AKT1 in human cancer tumors: it was discovered in clinical samples from cancer patients, yet has never been detected in cancer cell lines.

"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 Kerry L. Blanchard, PhD, MD, Executive Director, Discovery Biology Research, Eli Lilly & Company.

To identify the AKT1 mutation, the researchers analyzed 150 tumor samples from patients with either breast, colorectal or ovarian cancer (50 samples from each tumor type). Analysis of the data showed that 8 percent of breast, 6 percent of colorectal and 2 percent of ovarian tumors had the AKT1 mutation in the samples that were screened in their study.

"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 John Carpten, PhD, 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."

If validated by further studies, the identification of this recurring mutation has the potential to impact cancer treatment and drug development.

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

James E. Thomas, PhD, of Lilly's Cancer Discovery Research division, ex- plained, "AKT1 is a protein kinase or enzyme that plays a key role in activating survival, proliferation and metabolic pathways. Interestingly, other cellular proteins that regulate this network have also been shown to be mutated in a variety of cancers including lung, breast ovary, prostate, colorectal and brain cancers. This mutation in AKT1 is striking direct evidence for the role of AKT1 in cancer formation."

The identification of the AKT1 mutation was a collaborative effort between Eli Lilly & Company and TGen. "This discovery demonstrates the importance of studying the genetic make up of cancers at the clinical level rather than re- lying on model systems," adds Jeffrey Trent, PhD, Scientific Director of TGen.

"This is a key study highlighting Lilly's commitment to translational re- search approaches in cancer drug discovery and development. Furthermore, this work is a great example of a successful public-private partnership at a global level that involves Lilly Research Laboratories in Indianapolis, TGen in Phoenix, Lilly Singapore Centre for Drug Discovery, and the Economic Development Board of Singapore," adds Richard Gaynor, MD, Vice President of Oncology Discovery at Eli Lilly & Company. He added, "This mutation further validates AKT1 as an attractive drug target, and it also will be a valuable tool for the stratification of patients for targeted therapies. This paradigm of identifying specific defects in cancer cells to successfully develop innovative therapies has been validated with oncology drugs such as Gleevec in leukemia and Herceptin in breast cancer."