Case Study: Analyzing Tumor Cell Resistance Pathways with Single-Cell Intracellular Proteome

Multiple Pathways to Resistance Revealed in Mutant Melanoma Cells

Drug resistance can complicate cancer treatment strategies. Although several studies have attempted to elucidate the mechanisms of  therapy resistance in solid tumor via gene expression, this type of data cannot truly map the proteomic paths to resistance at the single-cell level. IsoPlexis’ Single-Cell Intracellular Proteome solution provides the missing data layer that enables the development of effective combination therapies. This solution uses high multiplexing and more specificity to map full networks of tumor cell pathways with 15+ analytes, going far beyond traditional methods that are capable of analyzing only a few analytes at a time.

In a study published in Nature Communications, “Multi-omic single-cell snapshots reveal multiple independent trajectories to drug tolerance in a melanoma cell line,” Su, et al. used a well-characterized melanoma cell line that is known to rapidly develop drug resistance, and employed multiple impactful analyses to reveal changes in functional phenotype over time in individual cells. Using IsoPlexis’ Single-Cell Intracellular Proteome/metabolome technology, this group was able to define multiple independent paths that tumor cells take in the development of drug resistance.

Drug Resistance in Cancer Therapy

The mutant melanoma cancer cells (BRAFV600E M397) were treated with BRAF inhibitor (BRAFi) each day for five days and analyzed with IsoPlexis’ technology each day. The group used a panel consisting of phenotypic markers and markers of oncogenic signaling, cell proliferation, and metabolic activity, which are all transformed in the preliminary drug response. On day 1, most metabolic regulators and phosphoprotein signaling was blocked, indicating that the BRAFi treatment was working. However, on day 3, many markers showed a sharp and temporary rise in variance, indicating multiple cell state changes at this point in time. By day 5, most cells had gone into a senescent state, with some cells moving toward mesenchymal phenotype.

Multiple pathways to drug resistance make targeting the resistance mechanism even more difficult, however, drug susceptibilities were identified for both pathways. IsoPlexis’ platform correctly predicted the combination therapy that would effectively combat this resistance by targeting both pathways. These data can now enable researchers to develop combination therapies to prevent this common drug-resistant cell state. To learn more about how the Single-Cell Intracellular Proteome solution revealed multiple druggable resistance pathways, read this blog post or the full summary of the publication.

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