Editors' ChoiceCancer Genomics

Made-by-measure

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Science Translational Medicine  01 Jun 2016:
Vol. 8, Issue 341, pp. 341ec89
DOI: 10.1126/scitranslmed.aag1705

To date, precision medicine efforts have relied on bulk genetic or epigenetic profiling of a tumor, masking differences between individual cancer cells that can drive drug resistance and relapse. Sequencing those same cells independently, rather than en masse, could reveal the various malignant cell states and pathways active in that tumor, promising a route toward novel and rationally selected therapeutic strategies. Now, Kim et al. have taken a big step toward realizing this vision in kidney cancer. By sequencing a total of 116 single cells from a lung metastasis of renal cell carcinoma as well as matched primary and metastatic patient-derived xenografts (PDXs), the authors uncovered heterogeneous and metastasis-specific variability in cellular activity across gene sets involved in common drug-target pathways, such as EGFR, Src/FAK, and c-MET. Using cells from the two PDXs, they confirmed that elevated activity across a pathway, on average, was linked with sensitivity to drugs targeting that same pathway. At the single-cell level, however, the authors observed variable, binary activation of some of these signaling pathways, such as EGFR and Src, across cells within the metastatic samples, suggesting that a combination anti-EGFR/anti-Src therapy might be more effective at eradicating the metastasis than either alone. Subsequent experiments in both metastatic cells ex vivo and the metastatic PDX mouse model in vivo confirmed that this combination therapy did, in fact, result in more substantial reductions in tumor cell viability.

Although the authors were not able to test their combination therapy on the original patient, their work supports the potential for designing precision medicines. Several steps remain, including extension to larger cohorts and other cancers, further development of drug target signatures, consideration of the nonmalignant cells that impact tumor drug responses, and realization of screening approaches that rapidly inform patient treatment selection. Nevertheless, it is increasingly clear that new diagnostic and therapeutic strategies that consider tumor composition rather than bulk properties will soon revolutionize cancer treatment.

K.-T. Kim et al., Application of single-cell RNA sequencing in optimizing a combinatorial therapeutic strategy in metastatic renal cell carcinoma. Genome Biol. 10.1186/s13059-016-0945-9 (2016). [Full Text]

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