Genome Sequencing Identifies a Basis for Everolimus Sensitivity

Gopa Iyer,^1,2,3 Aphrothiti J. Hanrahan,¹ Matthew I. Milowsky,^2,3 Hikmat Al-Ahmadie,⁴ Sasinya N. Scott,¹ Manickam Janakiraman,¹ Mono Pirun,⁵ Chris Sander,⁵ Nicholas D. Socci,⁶ Irina Ostrovnaya,⁷ Agnes Viale,⁸ Adriana Heguy,¹ Luke Peng,¹ Timothy A. Chan,¹ Bernard Bochner,⁹ Dean F. Bajorin,^2,3 Michael F. Berger,⁴ Barry S. Taylor,^5,*, David B. Solit^1,2,3,

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.

¹ Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
² Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
³ Department of Medicine, Weill Medical College of Cornell University, New York, NY 10065, USA.
⁴ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁵ Computational Biology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁶ Bioinformatics Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁷ Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁸ Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
⁹ Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

To whom correspondence should be addressed. E-mail: barry.taylor{at}ucsf.edu (B.S.T.); solitd{at}mskcc.org (D.B.S.)

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