Application of single-cell RNA sequencing in optimizing a combinatorial therapeutic strategy in metastatic renal cell carcinoma.
Kyu-Tae Kim, Hye Won Lee, Hae-Ock Lee, Hye Jin Song, Da Eun Jeong, Sang Shin, Hyunho Kim, Yoojin Shin, Do-Hyun Nam, Byong Chang Jeong, David G Kirsch, Kyeung Min Joo, Woong-Yang Park
Author Information
Kyu-Tae Kim: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
Hye Won Lee: Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea.
Hae-Ock Lee: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea.
Hye Jin Song: Departments of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea.
Da Eun Jeong: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
Sang Shin: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
Hyunho Kim: School of Mechanical Engineering, Korea University, Seoul, South Korea.
Yoojin Shin: School of Mechanical Engineering, Korea University, Seoul, South Korea.
Do-Hyun Nam: Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea.
Byong Chang Jeong: Departments of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
David G Kirsch: Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
Kyeung Min Joo: Departments of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. kmjoo@skku.edu.
Woong-Yang Park: Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. woongyang.park@samsung.com.
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.
