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Genome Biol. 2016 Apr 29;17:80. doi: 10.1186/s13059-016-0945-9.

Application of single-cell RNA sequencing in optimizing a combinatorial therapeutic strategy in metastatic renal cell carcinoma.

Author information

1
Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
2
Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.
3
Departments of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea.
4
Departments of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea.
5
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
6
School of Mechanical Engineering, Korea University, Seoul, South Korea.
7
Departments of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
8
Departments of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
9
Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
10
Departments of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
11
Departments of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. kmjoo@skku.edu.
12
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea. kmjoo@skku.edu.
13
Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. woongyang.park@samsung.com.
14
Departments of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. woongyang.park@samsung.com.
15
Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea. woongyang.park@samsung.com.

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.

KEYWORDS:

Drug response; Patient-derived xenograft; Renal cell carcinoma; Single cell analysis; Tumor heterogeneity

PMID:
27139883
PMCID:
PMC4852434
DOI:
10.1186/s13059-016-0945-9
[Indexed for MEDLINE]
Free PMC Article

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