One Step at a Time — Clinical Evidence that KRAS Is Indeed Druggable
Mené sur 129 patients atteints d’une tumeur solide de stade avancé présentant la mutation G12C du gène KRAS, cet essai de phase I évalue la dose maximale tolérée du sotorasib (un inhibiteur ciblant la protéine G12C de KRAS) et analyse ses caractéristiques pharmacocinétiques, après l’échec de plusieurs lignes de traitements (nombre médian de thérapies précédentes : 3)
Overall survival among patients with advanced-stage KRASG12C non–small-cell lung cancer (NSCLC) or colorectal cancer is approximately 1 to 2 years; this startling statistic has fueled nearly four decades of research dedicated to the search for a KRAS-targeted drug.1,2 Because RAS has picomolar affinity for guanosine triphosphate (GTP) and intracellular GTP concentrations are exceedingly high, early strategies to find compounds that preferentially bind to the RAS–GTP pocket failed. Other strategies have attempted to interfere with RAS activation by preventing its membrane localization or by inhibiting downstream kinase signaling, but these also failed because of resistance stemming from compensatory signaling. Renewed interest .(...)