Kyu-Tae Kim1†, Hye Won Lee2†, Hae-Ock Lee1,3, Hye Jin Song4, Da Eun Jeong5, Sang Shin5, Hyunho Kim6, Yoojin Shin6, Do-Hyun Nam5,7, Byong Chang Jeong8, David G. Kirsch9,10, Kyeung Min Joo4,5* and Woong-Yang Park1,3,5*
1Samsung Genome Institute, Samsung Medical Center, Seoul, South Korea. 2Institute for Future Medicine, Samsung Medical Center, Seoul, South Korea. 3Departments of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. 4Departments of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, South Korea. 5Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology, Sungkyunkwan University, Seoul, South Korea. 6School of Mechanical Engineering, Korea University, Seoul, South Korea.7Departments of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 8Departments of Urology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 9Departments of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA. 10Departments of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.
* Correspondence: Kyeung Min Joo; Woong-Yang Park
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.
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.
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 : Single cell analysis, Renal cell carcinoma, Patient-derived xenograft, Tumor heterogeneity, Drug response