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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Kim, K-T; Lee, HW; Lee, H-O; Song, HJ; Jeong, DE; Shin, S; Kim, H; Shin, Y; Nam, D-H; Jeong, BC; Kirsch, DG; Joo, KM; Park, W-Y

Published Date

  • April 29, 2016

Published In

Volume / Issue

  • 17 /

Start / End Page

  • 80 -

PubMed ID

  • 27139883

Pubmed Central ID

  • PMC4852434

Electronic International Standard Serial Number (EISSN)

  • 1474-760X

Digital Object Identifier (DOI)

  • 10.1186/s13059-016-0945-9


  • eng

Conference Location

  • England