title: RNA-seq reveals aurora kinase-driven mTOR pathway activation in patients with sarcomatoid metastatic renal cell carcinoma.
abstract: Sarcomatoid metastatic renal cell carcinoma (mRCC) is associated with a poor prognosis, and the biology of the disease has been inadequately characterized. RNA sequencing (RNA-seq) was performed on adjacent benign, clear cell, and sarcomatoid components from clinical specimens with sarcomatoid mRCC. M phase and cell-cycle pathways were enriched in sarcomatoid versus adjacent clear cell components, suggesting greater cell proliferation. The expression of aurora kinase A (AURKA) was increased as part of these pathways, and its increased expression was validated by quantitative PCR (qPCR). Immunohistochemical (IHC) analysis revealed that AURKA levels were increased in sarcomatoid tissue compared with their benign or clear cell parts. The increase in AURKA correlated with increased mTOR pathway activity, as evidenced by increased expression of phosphorylated mTOR (S2448) and ribosomal protein S6K (T389). When AURKA was stably expressed in a RCC cell line (Renca), it resulted in increased expression and activity of mTOR, suggesting that overexpression of AURKA can activate the mTOR pathway. These results warrant the analysis of a larger clinical cohort and suggest that targeting AURKA and/or mTOR in patients with sarcomatoid mRCC should be explored.
  
  
  CONCLUSIONS
  Comparative RNA-seq of adjacent sarcomatoid and clear cell histology of RCC indicates a proliferative phenotype and increased AURKA-dependent activation of mTOR signaling in sarcomatoid RCC, which could be targeted by available agents.
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Sumanta K
authors.initials: SK
authors.lastname: Pal
authors.affiliation: Department of Molecular Pharmacology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Miaoling
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Tommy
authors.initials: T
authors.lastname: Tong
authors.affiliation: Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Biostatistics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Xueli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Surgery, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Clayton
authors.initials: C
authors.lastname: Lau
authors.affiliation: Functional Genomics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Jin-Hui
authors.initials: JH
authors.lastname: Wang
authors.affiliation: Functional Genomics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Charles
authors.initials: C
authors.lastname: Warden
authors.affiliation: Functional Genomics, City of Hope Comprehensive Cancer Center, Duarte, California.
authors.forename: Xiwei
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology, Dana Farber Cancer Center, Boston, Massachusetts.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Center, Boston, Massachusetts.
authors.forename: Toni K
authors.initials: TK
authors.lastname: Choueiri
authors.affiliation: Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Karam
authors.affiliation: Department of Molecular Pharmacology, City of Hope Comprehensive Cancer Center, Duarte, California. jjones@coh.org.
authors.forename: Jeremy O
authors.initials: JO
authors.lastname: Jones
mesh_terms: D000328:Adult; D000368:Aged; D064096:Aurora Kinase A / Q000096:biosynthesis* / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012313:RNA / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D012313:RNA; C546842:MTOR protein, human; C576917:AURKA protein, human; D064096:Aurora Kinase A; D058570:TOR Serine-Threonine Kinases