Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signalling

• Published in: Nature communications Vol. 12; no. 1; pp. 1747 - 14
• Main Authors: Yang, Chen, Tian, Chengzhe, Hoffman, Timothy E, Jacobsen, Nicole K, Spencer, Sabrina L
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 19.03.2021; Nature Publishing Group UK; Nature Portfolio
• Subjects: Activating Transcription Factor 4; Anticancer properties; Cell Line, Tumor; Cell Proliferation; Cyclin-Dependent Kinase 2 - metabolism; Damage; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA damage; DNA Damage - drug effects; DNA Replication; Drug resistance; Genetic factors; Humans; Inhibitors; MAP kinase; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Mutagenesis; Mutation; Protein Kinase Inhibitors - pharmacology; Resistance factors; Signal transduction; Signal Transduction - drug effects; Signaling; Subpopulations; Transcriptome; Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-21549-x

Despite the increasing number of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance. While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug. Here we track the responses of thousands of single melanoma cells to BRAF inhibitors and show that a subset of cells escapes drug via non-genetic mechanisms within the first three days of treatment. Cells that escape drug rely on ATF4 stress signalling to cycle periodically in drug, experience DNA replication defects leading to DNA damage, and yet out-proliferate other cells over extended treatment. Together, our work reveals just how rapidly melanoma cells can adapt to drug treatment, generating a mutagenesis-prone subpopulation that expands over time.