Genome sequencing of an exceptional everolimus responder pinpoints TSC1 loss as the sensitivity basis.
| Evidence tier | B Direct human evidence |
| Study type | 3 - Human Observational |
| Model system | Human (patient) + sequencing |
| Journal | Science |
| Year | 2012 |
| Peer reviewed | Yes |
| Source | DOI 10.1126/science.1226344 · PMID 22923433 · Free full text (PMC3633467) |
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.
| Intervention | Everolimus (mTOR inhibitor) |
| Target | mTOR / TSC1 |
| Model | Human – metastatic bladder cancer patient + tumor sequencing |
| Effect | Loss-of-function TSC1 mutation explains an exceptional everolimus response; TSC1 mutated in ~8% of bladder cancers |