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Cancer Cell. 2018 Dec 10;34(6):954-969.e4. doi: 10.1016/j.ccell.2018.11.007.

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

Author information

1
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Thoracic Medicine, Chang Gung Foundation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; Department of Pulmonary and Critical Care Medicine Saint Paul's Hospital, Taoyuan City 33069, Taiwan; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
3
College of Medicine, Chang Gung University, Taoyuan 333, Taiwan; Department of Pathology, Chang Gung Foundation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan.
4
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Thoracic Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.
5
Department of Thoracic Medicine, Chang Gung Foundation, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan; College of Medicine, Chang Gung University, Taoyuan 333, Taiwan.
6
Division of Pulmonary and Critical Care Medicine, China Medical University and Hospital, Taichung 404, Taiwan; Department of Internal Medicine, China Medical University and Hospital, Taichung 404, Taiwan; School of Medicine, China Medical University, Taichung 404, Taiwan; Department of Life Science, National Chung-Hsing University, Taichung 402, Taiwan.
7
Division of Pulmonary and Critical Care Medicine, China Medical University and Hospital, Taichung 404, Taiwan; Department of Internal Medicine, China Medical University and Hospital, Taichung 404, Taiwan; Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan; Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
8
Center for Molecular Medicine and Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan.
9
Cancer Center, China Medical University, Taichung 404, Taiwan.
10
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China.
11
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Medical Oncology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung 333, Taiwan.
12
Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
13
Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
14
Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY 10016, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
15
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan.
16
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for Molecular Medicine and Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: mhung@mdanderson.org.

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.

KEYWORDS:

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

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