A novel, recurring mutation of the AKT1 gene in breast, colorectal, and ovarian cancer may have diagnostic potential if additional research shows that therapy targeting this polymorphism will confer a survival advantage in patients, according to an Eli Lilly official.
Lilly and the Phoenix-based non-profit Translational Genomics Research Institute announced last week that researchers had identified an altered form of AKT1 that appears to play a role in tumor cell proliferation and cell resistance to certain therapies.
Kerry Blanchard, executive director of discovery biology research at Lilly, told Pharmacogenomics Reporter this week that while there is potential for the development of a diagnostic based on these findings, the data needs to be validated in clinical trials for Lilly to move ahead in this direction. If additional research shows that an AKT1 targeted therapy could confer a survival advantage to patients, Lilly would then partner with a diagnostic company to develop a companion assay.
“We’re not a diagnostics company, and so we would partner with an outside group to develop a clinical diagnostic,” Blanchard said. “Over the next few months we will get more experience in a retrospective way, looking at samples that have already been collected on which we have clinical information [to assess] whether or not this mutation might confer a survival advantage or disadvantage to a patient population. That would make us more interested in developing [a diagnostic] further.”
In fact, since the study appeared in July 4, one diagnostic company and several academic organizations have contacted Lilly expressing interest in taking the research further.
According to Blanchard, a potential diagnostic for an AKT inhibitor would likely be based either on standard DNA sequencing technology or a PCR assay. “To develop an assay for detecting this mutation is fairly straightforward,” Blanchard said. “There are many that are done in the clinic now for other mutations like the EGFR mutations.”
John Carpten, director of TGen’s Integrated Cancer Genomics Division and the study’s lead author, said in a statement that the next step following this research is to determine the prevalence of the AKT1 mutation in different populations and use the data from clinical studies to stratify patients in clinical trials with AKT inhibitors.
Lilly is currently developing enzastaurin, an AKT inhibitor for non-Hodgkin’s lymphoma, and also looking into the compound’s activity in ovarian, prostate, lung, breast, and colorectal cancer.
The identification of the AKT1 mutation and the study was the result of a public-private partnership between Lilly and TGen. Researchers at TGen performed the DNA sequencing that led to the discovery of the AKT1 mutation, while a majority of the biology and structural work using cell-based and animal models was completed in Lilly Research Laboratories in Indianapolis.
The systems biology and the bioinformatics were performed at the Lilly Singapore Center for Drug Discovery.
The study, which was funded by Lilly and with a grant from the Economic Development Board of Singapore, identified a somatic mutation in human breast, colorectal, and ovarian cancers that causes “glutamic acid to lysine substitute at amino acid 17 (E17K) in the lipid-binding pocket of AKT1.”
According to Lilly and TGen researchers, the Lys 17 mutation “activates AKT1 by means of pathological localization to the plasma membrane, stimulates downstream signaling, transforms cells and induces leukemia in mice.”
The study findings suggest that AKT1 plays a direct role in human cancer and that the E17K substitution in patients decreases their sensitivity to an allosteric kinase inhibitor. “So this mutation may have important clinical utility for AKT drug development,” the researchers said.
Blanchard noted that the data is the best evidence of target validation of AKT1 and it may ultimately help guide therapy decisions for cancer patients.
According to scientific literature, the PI3-Kinase/AKT is a cellular pathway that is commonly activated in cancer, and activation of this pathway promotes cancer cell growth and survival.
However, until Lilly and TGen’s findings, the cellular pathway was largely thought to play an intermediary role between mutated upstream regulatory proteins and downstream survival signaling proteins, TGen said in a statement last week.
“Over the next few months we will get more experience in a retrospective way, looking at samples that have already been collected on which we have clinical information, [to assess] whether or not this mutation might confer a survival advantage or disadvantage to a patient population. That would make us more interested in developing [a diagnostic] further.”
“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,” the non-profit noted.
In order to identify the AKT1 mutation, researchers analyzed 150 tumor samples from breast, colorectal, or ovarian cancer patients. The study results showed that the AKT1 mutation was present in 8 percent of breast, 6 percent of colorectal, and 2 percent of ovarian cancer tumor samples.
The fact that the mutation’s role in cancer was discovered directly in human samples gives more credence to the view that it may be an important target in drug development. The samples “didn’t come from cell lines or animal models. It is a single-point mutation that is recurring. So, we have multiple examples in breast and colon cancer,” Blanchard said.
"This discovery demonstrates the importance of studying the genetic make up of cancers at the clinical level rather than relying on model systems," Jeffrey Trent, scientific director of TGen, said in a statement.
“I can tell you from the e-mail responses that I’ve had in the last week that there are many, many people interested in this mutation,” Blanchard said, adding that the interested organizations are located in various parts of Asia, Europe, and the US.
Ultimately, the international attention the research has garnered may help Lilly gauge the ethnic and geographic variations in the incidence of the mutation.
“I think we know from the EGFR experience that there are ethnic and geographic variations in the incidence of the mutation. It’s quite possible that it might be the same in the case” of AKT, Blanchard said. “This is why it’s important and why I’m so excited about having multiple investigators from all over the world call about this. ... They’ll test this in their own populations and we’ll know whether or not there is regional variation.”