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), researchers at the Samsung Genome Institute, South Korea 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, they 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.
Profiling transcriptome of paired pRCC and mRCC at single-cell resolution
a Brief description of clinical course in a patient with metastatic RCC. b Schematic of scRNA-seq experiments from establishment of the patient-derived xenograft model to discovery of targetable subpopulations. c Hierarchical clustering heatmap and dendrogram based on inter-correlation of centroid global expression profiles across kidney cortex normal, bulk cells of each population, and single cells using Euclidean distance metric and average linkage. d Principal component analysis (PCA) of single-cell-resolved gene expression profiles based on the first two principal components. Ellipses represent 95 % confidence around each group
These 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.