Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance.
The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired resistance after EGFR-TKI treatment, and primary resistance marked by cancer cell's dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Jeong Eun
JE
Lee
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Hee Sun
HS
Park
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Dahye
D
Lee
Department of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
Geon
G
Yoo
National Creative Research Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology(KAIST), Daejeon 34141, South Korea.
Tackhoon
T
Kim
National Creative Research Center for Cell Division and Differentiation, Department of Biological Sciences, Korea Advanced Institute of Science and Technology(KAIST), Daejeon 34141, South Korea.
Haeyon
H
Jeon
Department of Pathology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Min-Kyung
MK
Yeo
Department of Pathology, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Choong-Sik
CS
Lee
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Jae Young
JY
Moon
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Sung Soo
SS
Jung
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Ju Ock
JO
Kim
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Sun Young
SY
Kim
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Dong Il
DI
Park
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea.
Yeon Hee
YH
Park
Department of Oncology, College of Medicine, University of Ulsan Asan Medical Center, Seoul 138-736, South Korea.
Jae Cheol
JC
Lee
Department of Internal Medicine, Chonnam National University Hwasun Hospital 322 Seoyangro, Hwasun-eup, Hwasun, Jeonnam, 519-809, South Korea.
In-Jae
IJ
Oh
Department of Biological Sciences, Seoul National University, Seoul 151-742, South Korea.
Dae Sik
DS
Lim
Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon 35015, South Korea. Electronic address: universe7903@gmail.com.
Chaeuk
C
Chung
D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004815:Epidermal Growth Factor / Q000008:administration & dosage; D000090683:Hippo Signaling Pathway; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors; D016896:Treatment Outcome; D000091102:YAP-Signaling Proteins
D048868:Adaptor Proteins, Signal Transducing; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C017867:epidermal growth inhibitors; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases
EGFR; KRAS; Lung cancer; Resistance; YAP