Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer

Ying-Nai Wang; Heng-Huan Lee; Chao-Kai Chou; Wen-Hao Yang; Yongkun Wei; Chun-Te Chen; Jun Yao; Jennifer L Hsu; Cihui Zhu; Haoqiang Ying; Yuanqing Ye; Wei-Jan Wang; Seung-Oe Lim; Weiya Xia; How-Wen Ko; Xiuping Liu; Chang-Gong Liu; Xifeng Wu; Huamin Wang; Donghui Li; Laura R Prakash; Matthew H Katz; Yaan Kang; Michael Kim; Jason B Fleming; David Fogelman; Milind Javle; Anirban Maitra; Mien-Chie Hung

doi:10.1016/j.ccell.2018.02.012

Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer

Cancer Cell. 2018 Apr 9;33(4):752-769.e8. doi: 10.1016/j.ccell.2018.02.012. Epub 2018 Mar 29.

Authors

Ying-Nai Wang¹, Heng-Huan Lee², Chao-Kai Chou¹, Wen-Hao Yang², Yongkun Wei², Chun-Te Chen², Jun Yao², Jennifer L Hsu¹, Cihui Zhu², Haoqiang Ying³, Yuanqing Ye⁴, Wei-Jan Wang², Seung-Oe Lim², Weiya Xia², How-Wen Ko², Xiuping Liu⁵, Chang-Gong Liu⁵, Xifeng Wu⁶, Huamin Wang⁷, Donghui Li⁸, Laura R Prakash⁹, Matthew H Katz⁹, Yaan Kang⁹, Michael Kim⁹, Jason B Fleming⁹, David Fogelman¹⁰, Milind Javle¹⁰, Anirban Maitra¹¹, Mien-Chie Hung¹²

Affiliations

¹ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
² Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
³ Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA.
⁴ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁵ Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁶ Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA.
⁷ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
⁸ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA.
⁹ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁰ Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹¹ Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA.
¹² Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Unit 108, 1515 Holcombe Boulevard, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX 77030, USA; Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan; Department of Biotechnology, Asia University, Taichung 413, Taiwan. Electronic address: [email protected].

Abstract

Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families.

Keywords: EGFR inhibitor; EGFR ligand; PDAC; angiogenin; erlotinib; receptor tyrosine kinase; ribonuclease; serum biomarker.

Publication types

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

MeSH terms

Animals
Binding Sites
Biomarkers / blood
Carcinoma, Pancreatic Ductal / blood
Carcinoma, Pancreatic Ductal / drug therapy
Carcinoma, Pancreatic Ductal / pathology*
Cattle
Cell Line, Tumor
ErbB Receptors / chemistry
ErbB Receptors / metabolism
Erlotinib Hydrochloride / pharmacology*
Erlotinib Hydrochloride / therapeutic use
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
HeLa Cells
Humans
Mice
Neoplasm Transplantation
Pancreatic Neoplasms / blood
Pancreatic Neoplasms / drug therapy
Pancreatic Neoplasms / pathology*
Ribonuclease, Pancreatic / blood*
Ribonuclease, Pancreatic / chemistry
Ribonuclease, Pancreatic / metabolism*
Signal Transduction

Substances

Biomarkers
Erlotinib Hydrochloride
EGFR protein, human
ErbB Receptors
angiogenin
Ribonuclease, Pancreatic

Abstract

Publication types

MeSH terms

Substances

Grants and funding