Abstract
A new study of all 32 cancer types in The Cancer Genome Atlas identifies genomic alterations that increase the activity of the PI3K/AKT/mTOR pathway. The study, which combines mutation data with measures of protein levels and phosphorylation status, suggests that mutations in IDH1, VHL, and STK11 promote activation of the pathway and may point to new drug targets.
One of the first analyses of all 32 cancer types in The Cancer Genome Atlas (TCGA) has identified several genes with a surprisingly strong effect on the PI3K/AKT/mTOR pathway in human tumors, suggesting possible new drug targets for patients with alterations in this pathway.
Genes in the PI3K/AKT/mTOR pathway are frequently mutated in tumors. For example, PTEN, which encodes a protein that inhibits the pathway, is the second most commonly altered gene in cancers and is often deleted or carries multiple mutations. The pathway has been intensively studied, and inhibitors for some of its components are in use or under development. However, much of what researchers know about the effects of mutations on the pathway's activity comes from experiments on cell lines or animal studies.
To try to clarify the relevance of these mutations for human cancers, Chad Creighton, PhD, of Baylor College of Medicine in Houston, TX, and colleagues performed a proteogenomic analysis on TCGA data for 11,219 cancers from 32 tumor types, including breast invasive carcinoma, head and neck squamous cell carcinoma, and liver hepatocellular carcinoma. The scientists used this broad approach “to get a full picture of what the pathway is doing,” Creighton says. “We can appreciate how it is differently altered in different cancer types.”
For each cancer type, TCGA includes data from several platforms, such as whole-exome sequencing, whole-genome sequencing, and DNA copy number analysis. To gauge the pathway's activity, the researchers performed reverse-phase protein array analysis (RPPA), which indicates the levels of 166 proteins and the phosphorylation status of 56.
By correlating mutations with the RPPA results, the team identified changes that boost activity of the pathway. Although some of the alterations had turned up in previous studies, mutations stood out in two genes: IDH1 and VHL. Scientists typically don't consider either gene a core member of the PI3K/AKT/mTOR pathway. Creighton and colleagues note, however, that defects in the genes could spur the pathway's activation. Mutated IDH1 leads to production of the metabolite 2HG, which can activate mTOR. Also, recent research suggests that VHL may inhibit AKT.
The team's analysis of patient survival flagged another gene with unanticipated results: STK11, which encodes a protein that activates AMPK and curbs cell proliferation. STK11 is a core member of the mTOR pathway, but it had a powerful effect on survival. Across cancers, patients were about one third less likely to live for 4 years if they carried one mutated copy of STK11 and had lost the second than if they had two wild-type copies.
The study suggests that inhibitors of the PI3K/AKT/mTOR pathway could work for patients who have alterations in IDH1 or VHL, Creighton says.
The paper is a “must-read,” says Alex Toker, PhD, of Harvard Medical School in Boston, MA, who wasn't involved in the research. “It's one of the first studies that attempts to take the wealth of information from genetic and genomic approaches and overlay it with changes in proteins and phosphoproteins across thousands of human cancers.” The payoff from that approach, he says, is the identification of genes whose role in the PI3K/AKT/mTOR pathway is “unexpected or underappreciated” and that are potential treatment targets. –Mitch Leslie