Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway.

Abstract

Eradicating tumor dormancy that develops following epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment of EGFR-mutant non-small cell lung cancer, is an attractive therapeutic strategy but the mechanisms governing this process are poorly understood. Blockade of ERK1/2 reactivation following EGFR TKI treatment by combined EGFR/MEK inhibition uncovers cells that survive by entering a senescence-like dormant state characterized by high YAP/TEAD activity. YAP/TEAD engage the epithelial-to-mesenchymal transition transcription factor SLUG to directly repress pro-apoptotic BMF, limiting drug-induced apoptosis. Pharmacological co-inhibition of YAP and TEAD, or genetic deletion of YAP1, all deplete dormant cells by enhancing EGFR/MEK inhibition-induced apoptosis. Enhancing the initial efficacy of targeted therapies could ultimately lead to prolonged treatment responses in cancer patients.

• Authors: Kari J Kurppa, Yao Liu, Ciric To, Tinghu Zhang, Mengyang Fan, Amir Vajdi, Erik H Knelson, Yingtian Xie, Klothilda Lim, Paloma Cejas, Andrew Portell, Patrick H Lizotte, Scott B Ficarro, Shuai Li, Ting Chen, Heidi M Haikala, Haiyun Wang, Magda Bahcall, Yang Gao, Sophia Shalhout, Steffen Boettcher, Bo Hee Shin, Tran Thai, Margaret K Wilkens, Michelle L Tillgren, Mierzhati Mushajiang, Man Xu, Jihyun Choi, Arrien A Bertram, Benjamin L Ebert, Rameen Beroukhim, Pratiti Bandopadhayay, Mark M Awad, Prafulla C Gokhale, Paul T Kirschmeier, Jarrod A Marto, Fernando D Camargo, Rizwan Haq, Cloud P Paweletz, Kwok-Kin Wong, David A Barbie, Henry W Long, Nathanael S Gray, Pasi A Jänne
• Journal: Cancer cell (Cancer Cell) Vol. 37 Issue 1 Pg. 104-122.e12 (01 13 2020) ISSN: 1878-3686 [Electronic] United States
• PMID: 31935369 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Adaptor Proteins, Signal Transducing
• Cell Cycle Proteins
• Transcription Factors
• YAP-Signaling Proteins
• YAP1 protein, human
• Yap1 protein, mouse
• EGFR protein, human
• ErbB Receptors
• MAP Kinase Kinase 1

Topics

• Adaptor Proteins, Signal Transducing (metabolism)
• Animals
• Apoptosis
• Cell Cycle Proteins (metabolism)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cellular Senescence
• Drug Resistance, Neoplasm
• ErbB Receptors (metabolism)
• Female
• Gene Deletion
• Gene Expression Regulation, Neoplastic
• Humans
• Lung Neoplasms (metabolism, pathology)
• MAP Kinase Kinase 1 (metabolism)
• Male
• Mice
• Mice, Knockout
• Mutation
• Signal Transduction
• Transcription Factors (metabolism)
• Transcription, Genetic
• YAP-Signaling Proteins