Targeting PKCdelta
Menée in vitro et à l'aide de xénogreffes sur des modèles murins de cancer du poumon, cette étude met en évidence l'intérêt de cibler la protéine kinase C-delta pour lever la résistance aux inhibiteurs du récepteur EGFR des cellules cancéreuses porteuses d'une mutation au niveau du gène codant pour ce récepteur
Multiple mechanisms of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of nuclear protein kinase Cδ (PKCδ) as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.
Cancer Cell 2018