title: Application of single-cell RNA sequencing in optimizing a combinatorial therapeutic strategy in metastatic renal cell carcinoma.
abstract: BACKGROUND
  Intratumoral heterogeneity hampers the success of marker-based anticancer treatment because the targeted therapy may eliminate a specific subpopulation of tumor cells while leaving others unharmed. Accordingly, a rational strategy minimizing survival of the drug-resistant subpopulation is essential to achieve long-term therapeutic efficacy.
  
  
  RESULTS
  Using single-cell RNA sequencing (RNA-seq), we examine the intratumoral heterogeneity of a pair of primary renal cell carcinoma and its lung metastasis. Activation of drug target pathways demonstrates considerable variability between the primary and metastatic sites, as well as among individual cancer cells within each site. Based on the prediction of multiple drug target pathway activation, we derive a combinatorial regimen co-targeting two mutually exclusive pathways for the metastatic cancer cells. This combinatorial strategy shows significant increase in the treatment efficacy over monotherapy in the experimental validation using patient-derived xenograft platforms in vitro and in vivo.
  
  
  CONCLUSIONS
  Our findings demonstrate the investigational application of single-cell RNA-seq in the design of an anticancer regimen. The approach may overcome intratumoral heterogeneity which hampers the success of precision medicine.
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
authors.forename: Kyu-Tae
authors.initials: KT
authors.lastname: Kim
authors.affiliation: Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.
authors.forename: Hye Won
authors.initials: HW
authors.lastname: Lee
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.|Departments of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Hae-Ock
authors.initials: HO
authors.lastname: Lee
authors.affiliation: Departments of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Song
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
authors.forename: Da Eun
authors.initials: da E
authors.lastname: Jeong
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
authors.forename: Sang
authors.initials: S
authors.lastname: Shin
authors.affiliation: School of Mechanical Engineering, Korea University, Seoul, South Korea.
authors.forename: Hyunho
authors.initials: H
authors.lastname: Kim
authors.affiliation: School of Mechanical Engineering, Korea University, Seoul, South Korea.
authors.forename: Yoojin
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.|Departments of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.affiliation: Departments of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Byong Chang
authors.initials: BC
authors.lastname: Jeong
authors.affiliation: Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.|Departments of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch
authors.affiliation: Departments of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. kmjoo@skku.edu.|Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea. kmjoo@skku.edu.
authors.forename: Kyeung Min
authors.initials: KM
authors.lastname: Joo
authors.affiliation: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. woongyang.park@samsung.com.|Departments of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. woongyang.park@samsung.com.|Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea. woongyang.park@samsung.com.
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
mesh_terms: D000328:Adult; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002478:Cells, Cultured; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D017423:Sequence Analysis, RNA / Q000379:methods*; D059010:Single-Cell Analysis / Q000379:methods*
keywords: Drug response; Patient-derived xenograft; Renal cell carcinoma; Single cell analysis; Tumor heterogeneity