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

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 ChenLongfei Huo, Wen Hao Yang, Rong Deng, Katsuya Nakai, Yi Hsin Hsu, Shih Shin Chang, Tai Jan Chiu, Jun Tang, Ran Zhang, Li Wang, Bingliang Fang, Ting Chen, Kwok Kin Wong, Jennifer L. Hsu, Mien Chie Hung

Research output: Contribution to journalArticlepeer-review

53 Citations (Scopus)

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 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. Lee et al. find nuclear PKCδ as a mediator of resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs). TKI-induced EGFR heterodimerization promotes PKCδ nuclear translocation, which is associated with TKI resistance in patients. Combined TKI and PKCδ inhibition induces regression of resistant NSCLC tumors.

Original languageEnglish
Pages (from-to)954-969.e4
JournalCancer Cell
Volume34
Issue number6
DOIs
Publication statusPublished - Dec 10 2018

Keywords

  • EGFR
  • heterogeneity
  • heterogeneous mechanism of TKI resistance
  • heterogeneous resistance
  • lung cancer
  • PKC delta
  • PKCδ
  • resistance
  • TKI
  • tyrosine kinase inhibitor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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