Genomic Analysis of Smoothened Inhibitor 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
Smoothened (SMO) inhibitors are under clinical investigation for the treatment of several cancers. Vismodegib is approved for the treatment of locally advanced and metastatic basal cell carcinoma (BCC). Most BCC patients experience significant clinical benefit on vismodegib, but some develop resistance. Genomic analysis of tumor biopsies revealed that vismodegib resistance is associated with Hedgehog (Hh) pathway reactivation, predominantly through mutation of the drug target SMO and to a lesser extent through concurrent copy number changes in SUFU and GLI2. SMO mutations either directly impaired drug binding or activated SMO to varying levels. Furthermore, we found evidence for intra-tumor heterogeneity, suggesting that a combination of therapies targeting components at multiple levels of the Hh pathway is required to overcome resistance.
Cancer Cell , résumé, 2014