Targeting PKC? as a Therapeutic Strategy against Heterogeneous Mechanisms of EGFR Inhibitor Resistance in EGFR-Mutant Lung Cancer.

ABSTRACT: 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 C? (PKC?) 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 PKC? nuclear translocation. Moreover, the level of nuclear PKC? is associated with TKI response in patients. The combined inhibition of PKC? and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.

SUBMITTER: Lee PC 

PROVIDER: S-EPMC6886126 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature