title: RICTOR Amplification Defines a Novel Subset of Patients with Lung Cancer Who May Benefit from Treatment with mTORC1/2 Inhibitors.
abstract: We identified amplification of RICTOR, a key component of the mTOR complex 2 (mTORC2), as the sole actionable genomic alteration in an 18-year-old never-smoker with lung adenocarcinoma. Amplification of RICTOR occurs in 13% of lung cancers (1,016 cases) in The Cancer Genome Atlas and at a similar frequency in an independent cohort of 1,070 patients identified by genomic profiling. In the latter series, 11% of cases harbored RICTOR amplification as the only relevant genomic alteration. Its oncogenic roles were suggested by decreased lung cancer cell growth both in vitro and in vivo with RICTOR ablation, and the transforming capacity of RICTOR in a Ba/F3-cell system. The mTORC1/2 inhibitors were significantly more active against RICTOR-amplified lung cancer cells as compared with other agents targeting the PI3K-AKT-mTOR pathway. Moreover, an association between RICTOR amplification and sensitivities to mTORC1/2 inhibitors was observed. The index patient has been treated with mTORC1/2 inhibitors that led to tumor stabilization for more than 18 months.
  
  
  CONCLUSIONS
  RICTOR amplification may define a novel and unique molecular subset of patients with lung cancer who may benefit from treatment with mTORC1/2 inhibitors.
authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York. hcheng@montefiore.org.
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
authors.forename: Yiyu
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authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
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authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
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authors.affiliation: Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital-Columbia University Medical Center, New York, New York. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Xuewen
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York. Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital-Columbia University Medical Center, New York, New York.
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authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
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authors.affiliation: Departments of Genetics and Pathology, Molecular Cytogenetic Core, Albert Einstein College of Medicine, Bronx, New York.
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authors.affiliation: Division of Medical Oncology, NYU Langone Medical Center, New York, New York.
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
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authors.affiliation: Department of Pathology, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
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authors.affiliation: Departments of Genetics and Pathology, Molecular Cytogenetic Core, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Jidong
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
authors.forename: Yiting
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
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authors.affiliation: Foundation Medicine, Inc., Cambridge, Massachusetts.
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
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authors.affiliation: Division of Medical Oncology, Department of Medicine, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, New York.
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mesh_terms: D000293:Adolescent; D000367:Age Factors; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D055785:Gene Knockdown Techniques; D014644:Genetic Variation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; C492571:RICTOR protein, human; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases