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

• Published in: Translational oncology 2023-09, Vol.35, p.101722-101722, Article 101722
• Main Author: Merat, Rastine
• Format: Article
• Language: English
• Subjects: Adaptive resistance; Cell plasticity; HuR; melanoma; RNA-binding protein; Slow-cycling cell
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2023.101722

•Actionable hubs involved in cancer cell persistency and plasticity must be uncovered.•Phenotype-driven experimentally-fulfilled conditions validate mechanistic findings.•An experimental quantitative assessment of cell plasticity is proposed.•An information theory-based assessment of in vivo network dependencies is proposed.•Targeting HuR expression heterogeneity in BRAFV600-melanoma illustrates the strategy. 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-γ-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. [Display omitted]