Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Developmental Biology, Genetics & Heredity, DNA damage response, drug resistance, cellular dormancy, MAP kinase signaling, protein phosphatase 2A, small molecule inhibitor, RAF/MEK/ERK PATHWAY, CELL, MECHANISMS, INHIBITORS, DISCOVERY, GENE, Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, DNA Damage, Drug Resistance, Neoplasm, Humans, Melanoma, Protein Phosphatase 2, Pyrazoles, C16/19/006#55215869, 06 Biological Sciences, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, 31 Biological sciences, 32 Biomedical and clinical sciences, 52 Psychology

Abstract:

The emergence of drug resistance is a major obstacle for the success of targeted therapy in melanoma. Additionally, conventional chemotherapy has not been effective as drug-resistant cells escape lethal DNA damage effects by inducing growth arrest commonly referred to as cellular dormancy. We present a therapeutic strategy termed "targeted chemotherapy" by depleting protein phosphatase 2A (PP2A) or its inhibition using a small molecule inhibitor (1,10-phenanthroline-5,6-dione [phendione]) in drug-resistant melanoma. Targeted chemotherapy induces the DNA damage response without causing DNA breaks or allowing cellular dormancy. Phendione treatment reduces tumor growth of BRAFV600E-driven melanoma patient-derived xenografts (PDX) and diminishes growth of NRASQ61R-driven melanoma, a cancer with no effective therapy. Remarkably, phendione treatment inhibits the acquisition of resistance to BRAF inhibition in BRAFV600E PDX highlighting its effectiveness in combating the advent of drug resistance.