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

被引：67

作者：

Lee, Pei-Chih ^{[1
]}

Fang, Yueh-Fu ^{[1
,2
,3
,4
]}

Yamaguchi, Hirohito ^{[1
]}

Wang, Wei-Jan ^{[1
]}

Chen, Tse-Ching ^{[4
,5
]}

Hong, Xuan ^{[1
,6
]}

Ke, Baozhen ^{[1
]}

Xia, Weiya ^{[1
]}

Wei, Yongkun ^{[1
]}

Zha, Zhengyu ^{[1
]}

Wang, Yan ^{[1
]}

Kuo, Han-Pin ^{[2
,4
]}

Wang, Chih-Wei ^{[4
,5
]}

Tu, Chih-Yen ^{[7
,8
,9
,10
]}

Chen, Chia-Hung ^{[7
,8
,11
,12
]}

Huang, Wei-Chien ^{[13
,14
,15
]}

Chiang, Shu-Fen ^{[16
]}

Nie, Lei ^{[1
]}

Hou, Junwei ^{[1
]}

Chen, Chun-Te ^{[1
]}

Huo, Longfei ^{[1
]}

Yang, Wen-Hao ^{[1
]}

Deng, Rong ^{[1
,17
]}

Nakai, Katsuya ^{[1
]}

Hsu, Yi-Hsin ^{[1
]}

Chang, Shih-Shin ^{[1
]}

Chiu, Tai-Jan ^{[1
,18
]}

Tang, Jun ^{[1
,17
]}

Zhang, Ran ^{[19
]}

Wang, Li ^{[19
]}

Fang, Bingliang ^{[19
]}

Chen, Ting ^{[20
,21
]}

Wong, Kwok-Kin ^{[20
,21
,22
]}

Hsu, Jennifer L. ^{[1
,13
,14
,15
]}

Hung, Mien-Chie ^{[1
,13
,14
,15
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Chang Gung Mem Hosp, Chang Gung Fdn, Dept Thorac Med, Taoyuan 333, Taiwan

[3] St Pauls Hosp, Dept Pulm & Crit Care Med, Taoyuan 33069, Taiwan

[4] Chang Gung Univ, Coll Med, Taoyuan 333, Taiwan

[5] Chang Gung Mem Hosp, Chang Gung Fdn, Dept Pathol, Taoyuan 333, Taiwan

[6] Harbin Med Univ, Thorac Med Oncol, Canc Hosp, Harbin 150081, Heilongjiang, Peoples R China

[7] China Med Univ & Hosp, Div Pulm & Crit Care Med, Taichung 404, Taiwan

[8] China Med Univ & Hosp, Dept Internal Med, Taichung 404, Taiwan

[9] China Med Univ, Sch Med, Taichung 404, Taiwan

[10] Natl Chung Hsing Univ, Dept Life Sci, Taichung 402, Taiwan

[11] China Med Univ, Dept Resp Therapy, Taichung 404, Taiwan

[12] China Med Univ, Grad Inst Clin Med Sci, Taichung 404, Taiwan

[13] China Med Univ, Ctr Mol Med, Taichung 404, Taiwan

[14] China Med Univ, Grad Inst Biomed Sci, Taichung 404, Taiwan

[15] Asia Univ, Dept Biotechnol, Taichung 413, Taiwan

[16] China Med Univ, Canc Ctr, Taichung 404, Taiwan

[17] Sun Yat Sen Univ, Canc Ctr, State Key Lab Oncol South China, Guangzhou 510060, Guangdong, Peoples R China

[18] Chang Gung Univ, Coll Med, Kaohsiung Chang Gung Mem Hosp, Dept Med Oncol, Kaohsiung 333, Taiwan

[19] Univ Texas MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA

[20] NYU, Langone Med Ctr, Laura & Isaac Perlmutter Canc Ctr, Div Hematol & Med Oncol, New York, NY 10016 USA

[21] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[22] Dana Farber Canc Inst, Belfer Ctr Appl Canc Sci, Boston, MA 02215 USA

来源：

CANCER CELL | 2018年 / 34卷 / 06期

基金：

美国国家卫生研究院;

关键词：

PROTEIN-KINASE-C; ERLOTINIB RESISTANCE; ACQUIRED-RESISTANCE; BREAST-CANCER; EXPRESSION; TUMORS; PHOSPHORYLATION; TUMORIGENESIS; ACTIVATION; MUTATIONS;

D O I：

10.1016/j.ccell.2018.11.007

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 C delta (PKC delta) 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 PKC delta nuclear translocation. Moreover, the level of nuclear PKC delta is associated with TKI response in patients. The combined inhibition of PKC delta and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations.

引用

页码：954 / +

页数：20

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