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

Publication date: 13 January 2020Source: Cancer Cell, Volume 37, Issue 1Author(s): 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 ShalhoutSummaryEradicating 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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research