title: RICTOR amplification identifies a subgroup in small cell lung cancer and predicts response to drugs targeting mTOR.
abstract: Small cell lung cancer (SCLC) is an aggressive cancer that represents ~15% of all lung cancers. Currently there are no targeted therapies to treat SCLC. Our genomic analysis of a metastatic SCLC cohort identified recurrent RICTOR amplification. Here, we examine the translational potential of this observation. RICTOR was the most frequently amplified gene observed (~14% patients), and co-amplified with FGF10 and IL7R on chromosome 5p13. RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells. In parallel, cells with RICTOR copy number (CN) gain showed increased sensitivity to three mTOR inhibitors, AZD8055, AZD2014 and INK128 in cell growth assays, with AZD2014 demonstrating the best inhibition of downstream signaling. SCLC cells with RICTOR CN gain also migrated more rapidly in chemotaxis and scratch wound assays and were again more sensitive to mTOR inhibitors. The overall survival in SCLC patients with RICTOR amplification was significantly decreased (p = 0.021). Taken together, our results suggest that SCLC patients with RICTOR amplification may constitute a clinically important subgroup because of their potential response to mTORC1/2 inhibitors.
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106 USA.|Division of Hematology and Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, 44106 USA.
authors.forename: Nneha
authors.initials: N
authors.lastname: Sakre
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106 USA.|Division of Hematology and Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, 44106 USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Wildey
authors.affiliation: Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, 44106 USA.
authors.forename: Mohadese
authors.initials: M
authors.lastname: Behtaj
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106 USA.|Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, 44106 USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Kresak
authors.affiliation: Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, 44106 USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Yang
authors.affiliation: Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, 44106 USA.
authors.forename: Pingfu
authors.initials: P
authors.lastname: Fu
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, 44106 USA.|Division of Hematology and Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, 44106 USA.
authors.forename: Afshin
authors.initials: A
authors.lastname: Dowlati
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001549:Benzamides; D001583:Benzoxazoles / Q000494:pharmacology; D005260:Female; D051526:Fibroblast Growth Factor 10 / Q000235:genetics; D005784:Gene Amplification; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D000076226:Rapamycin-Insensitive Companion of mTOR Protein / Q000235:genetics*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome; D000225:Adenine / Q000031:analogs & derivatives
chemical_list: D001549:Benzamides; D001583:Benzoxazoles; D051526:Fibroblast Growth Factor 10; D053699:Interleukin-7 Receptor alpha Subunit; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; C496463:FGF10 protein, human; C000620371:IL7R protein, human; C492571:RICTOR protein, human; C585537:vistusertib; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; C572449:sapanisertib; D000225:Adenine
keywords: CNV; RICTOR; amplification; mTORC1/2 inhibitors; small cell lung cancer