Genome Sequencing Identifies a Basis for Everolimus Sensitivity
By G. Iyer, Aphrothiti J. Hanrahan, M. Milowsky, H. Al-Ahmadie, Sasinya N. Scott, M. Janakiraman, Mono Pirun, Christopher Sander, Nicholas D. Socci, I. Ostrovnaya and 9 more. Science, 2012
691 citations recorded by the source corpus.
Tumor genome sequencing reveals the molecular basis of a patient’s unexpected and dramatic response to a cancer drug. Cancer drugs often induce dramatic responses in a small minority of patients. We used whole-genome sequencing to investigate the genetic basis of a durable remission of metastatic bladder cancer in a patient treated with everolimus, a drug that inhibits the mTOR (mammalian target of rapamycin) signaling pathway. Among the somatic mutations was a loss-of-function mutation in TSC1 (tuberous sclerosis complex 1), a regulator of mTOR pathway activation. Targeted sequencing revealed TSC1 mutations in about 8% of 109 additional bladder cancers examined, and TSC1 mutation correlated with everolimus sensitivity. These results demonstrate the feasibility of using whole-genome sequencing in the clinical setting to identify previously occult biomarkers of drug sensitivity that can aid in the identification of patients most likely to respond to targeted anticancer drugs.
Subfields: Cancer Research, Physiology, Pulmonary and Respiratory Medicine
View Paper: https://www.semanticscholar.org/paper/c83b0ec997a5efbf9c87a3c88d14430297285462
How researchers see this paper
The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.
In Cancer Research
- David M. Sabatini
- Lewis C. Cantley
- R. Abraham
- R. A. Saxton
- S. Roychowdhury
- M. V. Vander Heiden
- Craig B. Thompson
In Physiology
In Pulmonary and Respiratory Medicine
Citations in the corpus
- Big Data for Health (2015, neutral): “tients [33], [34].”
- Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma (2014, neutral): “Onur Sumer(37), Nils Weinhold(37), Buck Institute for Research on Aging - Christopher Benz(38), University of Calif.”
- Lessons from the cancer genome. (2013, neutral): “For example, a recent tumor genomesequencing study of a bladder cancer patient who experienced a complete response to a TOR inhibitor (everolimus) identified two distinct cancer gene mutations (TSC1 and NF2) predicted to affect oncogenic TOR signaling (Iyer et al., 2012).”
- The PI3K pathway in human disease (2017, positive): “…sequencing to identify somatic mutations in TSC1 in patients with metastatic bladder cancer and observed that these patients Cell 170 , August 10, 2017 625 fared significantly better on everolimus therapy than did patients whose bladder tumors contained the wild-type TSC1 gene (Iyer et al., 2012).”
- Precision Cancer Medicine: Challenges and Opportunities (2019, background): “As of 2015, the cost of sequencing a single genome has dropped to $1245 [2], a cost comparable to many routine diagnostic tests, and the procedure can take as little as 26 hours from data acquisition to preliminary interpretation [3].”
- mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Even in these cases, however, an exquisite initial response has been followed by additional mutations in the kinase or FRB domains of MTOR, leading to acquired resistance (Wagle et al., 2014b).”