Abstract LB-092: TKI insensitive role of EGFRconfers TKI resistance via PKCδ

Abstract

Abstract EGFR TKI-insensitive pathway confers heterogeneous mechanisms of TKI resistance via PKCδ in EGFR-mutant lung cancer. Multiple mechanisms of resistance to 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 EGFR heterodimer-mediated nuclear 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 upregulated in a significant portion of patients (~41.5%) with TKI-resistant NSCLC and is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations. These results provide mechanistic insights into the role of the EGFR-PKCδ axis in TKI-resistance and suggest an EGFR addiction in TKI-resistant EGFR-mutant NSCLC. Citation Format: Pei-chih Lee, Mien-chie Hung. TKI insensitive role of EGFRconfers TKI resistance via PKCδ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-092.