American Association for Cancer Research
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Figure S8 from Single-Cell Profiling Reveals Metabolic Reprogramming as a Resistance Mechanism in BRAF-Mutated Multiple Myeloma

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posted on 2023-03-31, 23:05 authored by Johannes M. Waldschmidt, Jake A. Kloeber, Praveen Anand, Julia Frede, Antonis Kokkalis, Valeriya Dimitrova, Sayalee Potdar, Monica S. Nair, Tushara Vijaykumar, Nam Gyu Im, Amy Guillaumet-Adkins, Nitish Chopra, Hannah Stuart, Lillian Budano, Noori Sotudeh, Guangwu Guo, Clemens Grassberger, Andrew J. Yee, Jacob P. Laubach, Paul G. Richardson, Kenneth C. Anderson, Noopur S. Raje, Birgit Knoechel, Jens G. Lohr

Copy number variations in dabrafenib-persistent U266 single-cell clones as compared to baseline

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German Research Foundation

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ARTICLE ABSTRACT

Although remarkably effective in some patients, precision medicine typically induces only transient responses despite initial absence of resistance-conferring mutations. Using BRAF-mutated myeloma as a model for resistance to precision medicine we investigated if BRAF-mutated cancer cells have the ability to ensure their survival by rapidly adapting to BRAF inhibitor treatment. Full-length single-cell RNA (scRNA) sequencing (scRNA-seq) was conducted on 3 patients with BRAF-mutated myeloma and 1 healthy donor. We sequenced 1,495 cells before, after 1 week, and at clinical relapse to BRAF/MEK inhibitor treatment. We developed an in vitro model of dabrafenib resistance using genetically homogeneous single-cell clones from two cell lines with established BRAF mutations (U266, DP6). Transcriptional and epigenetic adaptation in resistant cells were defined by RNA-seq and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq). Mitochondrial metabolism was characterized by metabolic flux analysis. Profiling by scRNA-seq revealed rapid cellular state changes in response to BRAF/MEK inhibition in patients with myeloma and cell lines. Transcriptional adaptation preceded detectable outgrowth of genetically discernible drug-resistant clones and was associated with widespread enhancer remodeling. As a dominant vulnerability, dependency on oxidative phosphorylation (OxPhos) was induced. In treated individuals, OxPhos was activated at the time of relapse and showed inverse correlation to MAPK activation. Metabolic flux analysis confirmed OxPhos as a preferential energetic resource of drug-persistent myeloma cells. This study demonstrates that cancer cells have the ability to rapidly adapt to precision treatments through transcriptional state changes, epigenetic adaptation, and metabolic rewiring, thus facilitating the development of refractory disease while simultaneously exposing novel vulnerabilities.

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