Abstract
Abstract Targeted therapy that inhibits the BRAF (V600E) protein has shown impressive initial responses in metastatic melanoma patients. However, acquired drug resistance, derived from tumor heterogeneity, always limits its efficacy and compromises its treatment outcomes. Melanocyte to neural crest transition (MNT) has been observed to play crucial role in early stage adaptive drug tolerance, and the mathematic modeling indicates the transition is contributed from both stochastic phenotypic transition and non-genetic selection. Whole transcriptomic analysis enriched important signaling proteins that are involved in the resistance development process. Single cell proteomic analysis of those proteins was performed on patient-derived melanoma models to further study the early stage drug tolerance. This resolves how protein signaling network coordination rewires in the process, which cannot be resolved from proteomic analysis of bulk tumor tissue. Signaling network coordination analysis indicates that co-inhibiting the hubs of the network (MEK, NFKB-p65) could keep cells in the drug-susceptible stages. The combination therapy that co-inhibits mutant BRAF, MEK and NFKB-p65 together successfully arrested the MNT transition and induced a sustained tumor growth suppression in multiple patient-derived melanoma cell lines. This study provides us a brand-new way of using single cell proteomic analysis to infer effective combinations by resolving protein signaling network coordination that is inaccessible through traditional bulk-level proteomic measurement. Citation Format: Yapeng Su, Wei Wei, Min Xue, Lidia Robert, Jennifer Tsoi, Thomas Graeber, Antoni Ribas, James Heath. Single cell analysis resolves combinatory targeted therapy for arresting the BRAFi-induced cellular dedifferentiation of metastatic melanomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 879.
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