title: Genome sequencing identifies a basis for everolimus sensitivity.
abstract: 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.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Gopa
authors.initials: G
authors.lastname: Iyer
authors.forename: Aphrothiti J
authors.initials: AJ
authors.lastname: Hanrahan
authors.forename: Matthew I
authors.initials: MI
authors.lastname: Milowsky
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.forename: Sasinya N
authors.initials: SN
authors.lastname: Scott
authors.forename: Manickam
authors.initials: M
authors.lastname: Janakiraman
authors.forename: Mono
authors.initials: M
authors.lastname: Pirun
authors.forename: Chris
authors.initials: C
authors.lastname: Sander
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.forename: Agnes
authors.initials: A
authors.lastname: Viale
authors.forename: Adriana
authors.initials: A
authors.lastname: Heguy
authors.forename: Luke
authors.initials: L
authors.lastname: Peng
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
authors.forename: Bernard
authors.initials: B
authors.lastname: Bochner
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D018389:Codon, Nonsense; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000068338:Everolimus; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D058990:Molecular Targeted Therapy; D046912:Multiprotein Complexes; D009362:Neoplasm Metastasis; D025581:Neurofibromin 2 / Q000235:genetics; D011506:Proteins / Q000037:antagonists & inhibitors; D017384:Sequence Deletion; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D018389:Codon, Nonsense; D046912:Multiprotein Complexes; D025581:Neurofibromin 2; D011506:Proteins; C000624650:TSC1 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus