• National Cancer Institute
  • National Human Genome Research Institute

Posted: June 26, 2014

MTOR Gene Unlocks Two Approaches to Targeted Therapies

Jean Hazel Mendoza

Once in a while, a drug that seems to have failed all others saves a rare few. The success of a drug in so-called miracle patients, known as exceptional responders, has long baffled doctors. Why do some drugs prove powerful for some, but not for others? The answer may lie in the genome, according to two studies on a gene called MTOR, both published May 2014 in Cancer Discovery. By studying the interplay between drugs and the genes that they target, researchers are now beginning to understand the genetic basis underlying dramatic recoveries, in hopes of replicating this success in other patients.

The MTOR gene produces the protein mTOR, short for the mammalian target of rapamycin, which is a drug known to block its function.1 mTOR regulates cells’ ability to grow by mobilizing other molecules toward cell growth as part of a larger signaling pathway known as the PI3K-AKT-mTOR pathway. This pathway strongly activates in cancer, leading to abnormal cell growth and proliferation. While mutations in many genes of the pathway have been well-studied, few mutations have been uncovered in the MTOR gene itself.

A Catalog of MTOR Mutations

In the first study of its kind, researchers compiled a comprehensive catalog of mutations in the PI3K-AKT-mTOR pathway. The team, led by David M. Sabatini, M.D., Ph.D., of Whitehead Institute for Biomedical Research, analyzed the genomes of more than 400 patient samples from multiple tumor types, many from The Cancer Genome Atlas (TCGA). They discovered that every gene in the pathway is mutated, but none more so than MTOR, which contained 33 mutations. By comparing cancer cells that harbored these mutations with those that did not, they found that many of the mutations pushed the pathway into overdrive.

The mutations clustered in six distinct regions of the protein. One cluster in particular, called the C1483 cluster, appeared most prominently in kidney cancer compared with other tumor types. Indeed, recent genome characterization studies by TCGA2 and another led by The University of Tokyo3 both identified MTOR and other genes of the PI3K-AKT-mTOR pathway as significantly mutated in kidney cancer. Upon closer examination, Dr. Sabatini’s group determined that mutations in the C1483 cluster of MTOR boosted pathway activity.

Furthermore, the scientists tested the effects of the mTOR inhibitor rapamycin, shown to be effective against some human cancers, on MTOR. The drug shut down tumor growth in cancer cell lines as well as in mice carrying the mutations. This finding suggests that patients harboring these mutations could potentially benefit from therapeutic use of rapamycin and other mTOR inhibitors.

Solving a Case of Exceptional Response

Genome characterization and functional studies like Dr. Sabatini’s analyze cancer patients’ genomes to figure out the mutations driving the disease and to predict which drugs could potentially target them. This approach is known as a genotype-to-phenotype study, referring to an individual’s genome and the way it is outwardly expressed, respectively. The opposite approach, called a phenotype-to-genotype or an extreme responder study, works backwards. It begins with identifying a patient who has shown extraordinary response to a drug and examines the patient’s genome to find the mutations underpinning this sensitivity.4

This was the approach taken by a group led by Levi A. Garraway, M.D., Ph.D., of the Dana-Farber Cancer Institute and the Broad Institute of MIT and Harvard, and Jonathan E. Rosenberg, M.D., of Memorial Sloan Kettering Cancer Center. In the second report in Cancer Discovery, they conducted an early phase clinical trial of everolimus, an mTOR inhibitor like rapamycin, and pazopanib, an inhibitor of a variety of proteins other than mTOR.

Of the nine patients with advanced solid tumors in the trial, one patient with urothelial bladder cancer recovered dramatically. The patient’s tumors disappeared, a response that lasted for 14 months. To find out why everolimus and pazopanib proved so effective, the team looked at the whole-exome sequence of the exceptional responder’s pretreatment tumor and normal tissue.

Their analysis uncovered two mutations in MTOR called E2419K and E2014K. While the former has been well-studied in yeast, neither has been previously described in human cancer. In cell line studies, the researchers found that cancer cells containing each mutation aberrantly activated the PI3K-AKT-mTOR pathway, and cells with both mutations boosted the pathway even more than did either one alone. The team suggested that these mutations might be making the tumor especially dependent on the pathway, and thus remarkably vulnerable when targeted by the mTOR inhibitor everolimus. (Because of pazopanib’s extremely low dose in the trial and the fact that it does not target mTOR, the researchers concluded it played less of a role than did everolimus.)

Two Approaches Converge

These two mirror approaches, genotype-to-phenotype and extreme responder, are complimentary. The first study identified novel mutations in the MTOR gene, opening candidate targets for cancer drugs. The second study revealed two MTOR mutations that potentially underlie a patient’s remarkable response to everolimus. Together, they help advance the development of targeted therapies tailored to patients’ genetic profiles, which is the cornerstone of precision medicine.


Grabiner, B.C., Nardi, V., Birsoy, K., Possemato, R., Shen, K., Sinha, S., Jordan, A., Beck, A.H., and Sabatini, D.M. (2014) A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 4(5):554-563. View PubMed abstract

Wagle, N., Grabiner, B.C., Van Allen, E.M., Hodis, E., Jacobus, S., Supko, J.G., Stewart, M., Choueiri, T.K., Gandhi, L., Cleary, J.M., et al. (2014) Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 4(5):546-53. Read the full article

Selected References

1 Guertin, D.A., and Sabatini, D.M. (2007) Defining the role of mTOR in cancer. Cancer Cell. 12(1):9-22. Read the full article

2 The Cancer Genome Atlas Research Network. (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 499(7456):43-49. Read the full article

3 Sato, Y., Yoshizato, T., Shiraishi, Y., Maekawa, S., Okuno, Y., Kamura, T., Shimamura, T., Sato-Otsubo, A., Nagae, G., Suzuki, H., et al. (2013) Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 45(8):860-867. View PubMed abstract

4 Rejto, P.A., and Abraham, R.T. (2014) MTOR mutations in the crosshairs of targeted therapy. Cancer Discov. 4(5):513-515. View PubMed abstract