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, explained, “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 relying on model systems,” adds Jeffrey Trent, PhD, Scientific Director of TGen.
“This is a key study highlighting Lilly’s commitment to translational research 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.”
Two Group A Streptococcus genes linked to 'flesh-eating' bacterial infections
25.09.2017 | University of Maryland
Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden
At the productronica trade fair in Munich this November, the Fraunhofer Institute for Laser Technology ILT will be presenting Laser-Based Tape-Automated Bonding, LaserTAB for short. The experts from Aachen will be demonstrating how new battery cells and power electronics can be micro-welded more efficiently and precisely than ever before thanks to new optics and robot support.
Fraunhofer ILT from Aachen relies on a clever combination of robotics and a laser scanner with new optics as well as process monitoring, which it has developed...
Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.
A warming planet
Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.
The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...
Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...
Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!
When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...
19.09.2017 | Event News
12.09.2017 | Event News
06.09.2017 | Event News
25.09.2017 | Power and Electrical Engineering
25.09.2017 | Health and Medicine
25.09.2017 | Physics and Astronomy