The human antigen R as an actionable super-hub within the network of cancer cell persistency and plasticity

• Published in: arXiv.org 2023-06
• Main Author: Merat, Rastine
• Format: Article
• Language: English
• Subjects: Cancer; Gene expression; Information theory; Interferon; Melanoma
• ISSN: 2331-8422
• DOI: 10.48550/arxiv.2212.03290

In this perspective article, a clinically inspired phenotype-driven experimental approach is put forward to address the challenge of the adaptive response of solid cancers to small-molecule targeted therapies. A list of conditions is derived, including an experimental quantitative assessment of cell plasticity and an information theory-based detection of in vivo dependencies, for the discovery of post-transcriptional druggable mechanisms capable of preventing at multiple levels the emergence of plastic dedifferentiated slow-proliferating cells. The approach is illustrated by the author's own work in the example case of the adaptive response of BRAFV600-melanoma to BRAF inhibition. A bench-to-bedside and back to bench effort leads to a therapeutic strategy in which the inhibition of the baseline activity of the interferon-gamma-activated inhibitor of translation (GAIT) complex, incriminated in the expression insufficiency of the RNA-binding protein HuR in a minority of cells, results in the suppression of the plastic, intermittently slow-proliferating cells involved in the adaptive response. A similar approach is recommended for the validation of other classes of mechanisms that we seek to modulate to overcome this complex challenge of modern cancer therapy.