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

Publication date: 10 December 2018Source: Cancer Cell, Volume 34, Issue 6Author(s): Pei-Chih Lee, Yueh-Fu Fang, Hirohito Yamaguchi, Wei-Jan Wang, Tse-Ching Chen, Xuan Hong, Baozhen Ke, Weiya Xia, Yongkun Wei, Zhengyu Zha, Yan Wang, Han-Pin Kuo, Chih-Wei Wang, Chih-Yen Tu, Chia-Hung Chen, Wei-Chien Huang, Shu-Fen Chiang, Lei Nie, Junwei Hou, Chun-Te ChenSummaryMultiple 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research