Reference Detail

Ref Type

Journal Article

PMID

(22923433)

Authors

Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB

Title

Genome sequencing identifies a basis for everolimus sensitivity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Science (New York, N.Y.)	338	6104	2012 Oct 12	221	Science

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance
TSC1	V220F	missense	unknown	TSC1 V220F does not lie within any known functional domains of the Tsc1 protein (UniProt.org). V220F has been identified in the scientific literature (PMID: 22923433), but has not been biochemically characterized and therefore, its effect on Tsc1 protein function is unknown (PubMed, Nov 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TSC1 E636fs	bladder carcinoma	sensitive	Everolimus	Case Reports/Case Series	Actionable	A retrospective study of a Phase II trial correlated increased sensitivity to the mTOR inhibitor Afinitor (everolimus) with TSC1 mutations in bladder cancer patients, including one patient harboring TSC1 E636fs* who had a durable complete response (PMID: 22923433).	22923433
TSC1 mutant	bladder carcinoma	sensitive	Everolimus	Phase II	Actionable	A retrospective study of a Phase II trial correlated increased sensitivity to the mTOR inhibitor Afinitor (everolimus) with TSC1 mutations in bladder cancer patients (PMID: 22923433).	22923433