Differential patterns of protein expression in monolayer or spheroid melanoma cell models of acquired resistance to BRAF and MEK1/2 inhibitors

ABSTRACT: Mitogen activated protein kinase (MAPK) inhibitors are important therapies for treating many cancers. However, the development of acquired resistance to most protein kinase inhibitors limit their ability to provide durable responses. Approximately 50% of malignant melanomas contain activating mutations in the BRAF kinase, which promote cancer cell survival by activating the extracellular signal-regulated kinase-1/2 (ERK1/2) pathway through direct phosphorylation of the MAPK/ERK kinase-1/2 (MEK1/2). Although combination treatment with BRAF and MEK1/2 inhibitors is a recommended approach to treat melanoma, the development of drug resistance remains a barrier to achieving long term patient benefits. Using high-resolution label-free mass spectrometry, the current studies compared relative protein changes in BRAF and MEK1/2 inhibitor resistant A375 melanoma cells grown as monolayers or 3D spheroids. While approximately 66% of proteins identified were common in both monolayer and spheroid cultures, only 6.2% or 3.6% of proteins that significantly increased or decreased, respectively, compared to drug sensitive cells were common between the drug-resistant monolayer and spheroid cells. Major changes in drug-resistant monolayers suggested upregulation of alternative kinase signaling pathways that promote growth and metastasis. In contrast, the major changes in drug-resistant spheroids indicated increased catabolic metabolism to support oxidative phosphorylation and energy requirements.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Weiliang Huang  

LAB HEAD: Maureen Kane

PROVIDER: PXD026952 | Pride | 2022-02-17

REPOSITORIES: Pride