  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.
