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

• Published in: Cancer cell Vol. 37; no. 1; pp. 104 - 122.e12
• Main Authors: Kurppa, Kari J., Liu, Yao, To, Ciric, Zhang, Tinghu, Fan, Mengyang, Vajdi, Amir, Knelson, Erik H., Xie, Yingtian, Lim, Klothilda, Cejas, Paloma, Portell, Andrew, Lizotte, Patrick H., Ficarro, Scott B., Li, Shuai, Chen, Ting, Haikala, Heidi M., Wang, Haiyun, Bahcall, Magda, Gao, Yang, Shalhout, Sophia, Boettcher, Steffen, Shin, Bo Hee, Thai, Tran, Wilkens, Margaret K., Tillgren, Michelle L., Mushajiang, Mierzhati, Xu, Man, Choi, Jihyun, Bertram, Arrien A., Ebert, Benjamin L., Beroukhim, Rameen, Bandopadhayay, Pratiti, Awad, Mark M., Gokhale, Prafulla C., Kirschmeier, Paul T., Marto, Jarrod A., Camargo, Fernando D., Haq, Rizwan, Paweletz, Cloud P., Wong, Kwok-Kin, Barbie, David A., Long, Henry W., Gray, Nathanael S., Jänne, Pasi A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 13.01.2020
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis; Cell Cycle Proteins - metabolism; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cellular Senescence; dormancy; drug resistance; Drug Resistance, Neoplasm; drug tolerance; epidermal growth factor receptor; ErbB Receptors - metabolism; Female; Gene Deletion; Gene Expression Regulation, Neoplastic; Humans; lung cancer; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; MAP Kinase Kinase 1 - metabolism; Mice; Mice, Knockout; Mutation; senescence; Signal Transduction; Transcription Factors - metabolism; Transcription, Genetic; YAP; YAP-Signaling Proteins; lung cancer; senescence; epidermal growth factor receptor; dormancy; YAP; drug resistance; drug tolerance
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2019.12.006

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. [Display omitted] •Loss of EGFR signaling leads to senescence-like dormancy in EGFR-mutant lung cancer•YAP promotes survival and dormancy in the absence of EGFR downstream signaling•YAP/TEAD/SLUG suppress apoptosis through transcriptional repression of BMF•A TEAD inhibitor enhances EGFR inhibitor-mediated apoptosis and prevents dormancy Kurppa et al. show that YAP activation mediates resistance to combined EGFR/MEK inhibition by inducing dormancy in non-small-cell lung cancer cells. Targeting the YAP pathway, in part by using a newly developed covalent TEAD inhibitor, promotes apoptosis of the dormant therapy-resistant cancer cells.