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 Chen; Longfei 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

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

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

Authors

Pei-Chih Lee¹, Yueh-Fu Fang², Hirohito Yamaguchi¹, Wei-Jan Wang¹, Tse-Ching Chen³, Xuan Hong⁴, Baozhen Ke¹, Weiya Xia¹, Yongkun Wei¹, Zhengyu Zha¹, Yan Wang¹, Han-Pin Kuo⁵, Chih-Wei Wang³, Chih-Yen Tu⁶, Chia-Hung Chen⁷, Wei-Chien Huang⁸, Shu-Fen Chiang⁹, Lei Nie¹, Junwei Hou¹, Chun-Te Chen¹, Longfei Huo¹, Wen-Hao Yang¹, Rong Deng¹⁰, Katsuya Nakai¹, Yi-Hsin Hsu¹, Shih-Shin Chang¹, Tai-Jan Chiu¹¹, Jun Tang¹⁰, Ran Zhang¹², Li Wang¹², Bingliang Fang¹², Ting Chen¹³, Kwok-Kin Wong¹⁴, Jennifer L Hsu¹⁵, Mien-Chie Hung¹⁶

Affiliations

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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Adult
Aged
Aged, 80 and over
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Nucleus / genetics
Cell Nucleus / metabolism
Cell Survival / drug effects
Cell Survival / genetics
Drug Resistance, Neoplasm / drug effects*
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
ErbB Receptors / metabolism
Female
Humans
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology
Male
Microscopy, Confocal
Middle Aged
Molecular Targeted Therapy / methods
Mutation
Protein Kinase C-delta / antagonists & inhibitors*
Protein Kinase C-delta / metabolism
Protein Kinase Inhibitors / pharmacology*
RNA Interference

Substances

Protein Kinase Inhibitors
EGFR protein, human
ErbB Receptors
Protein Kinase C-delta

Grants and funding

P30 CA016672/CA/NCI NIH HHS/United States