Smoothened Variants Explain the Majority of Drug Resistance in Basal Cell Carcinoma
A partir de l'analyse de 44 échantillons tumoraux prélevés sur des patients atteints d'un carcinome basocellulaire ayant développé une résistance au vismodegib (un inhibiteur de SMO), puis in vitro, cette étude met en évidence des mécanismes par lesquels, via la régulation de la signalisation Hedgehog, certains variants du gène SMO favorisent la résistance thérapeutique
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and four variants conferring constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. In the presence of a SMO inhibitor, tumor cells containing either class of SMO mutants effectively outcompete cells containing the wild-type SMO. Finally, we show that both classes of SMO variants respond to aPKC-?/? or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
Cancer Cell , résumé, 2014