Treatment-Induced Tumor Dormancy through YAP-Mediated Transcriptional Reprogramming of the Apoptotic Pathway PMID: 31935369

ADC Targets in Oncology

2026-04-10

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

Cancer Cell. 2020 Jan 13;37(1):104-122.e12. doi: 10.1016/j.ccell.2019.12.006.

Kari J Kurppa ¹ , Yao Liu ² , Ciric To ¹ , Tinghu Zhang ² , Mengyang Fan ² , Amir Vajdi ³ , Erik H Knelson ¹ , Yingtian Xie ⁴ , Klothilda Lim ⁴ , Paloma Cejas ⁴ , Andrew Portell ⁵ , Patrick H Lizotte ⁵ , Scott B Ficarro ⁶ , Shuai Li ⁷ , Ting Chen ⁷ , Heidi M Haikala ¹ , Haiyun Wang ⁸ , Magda Bahcall ¹ , Yang Gao ⁹ , Sophia Shalhout ¹⁰ , Steffen Boettcher ¹¹ , Bo Hee Shin ¹ , Tran Thai ¹ , Margaret K Wilkens ¹² , Michelle L Tillgren ¹² , Mierzhati Mushajiang ¹ , Man Xu ⁵ , Jihyun Choi ¹ , Arrien A Bertram ¹ , Benjamin L Ebert ¹³ , Rameen Beroukhim ¹⁴ , Pratiti Bandopadhayay ¹⁵ , Mark M Awad ¹ , Prafulla C Gokhale ¹⁶ , Paul T Kirschmeier ⁵ , Jarrod A Marto ⁶ , Fernando D Camargo ¹⁰ , Rizwan Haq ¹⁷ , Cloud P Paweletz ⁵ , Kwok-Kin Wong ⁷ , David A Barbie ¹ , Henry W Long ⁴ , Nathanael S Gray ² , Pasi A Jänne ¹⁸

Affiliations

1. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA.
2. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
3. Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
5. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6. Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02215, USA.
7. Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
8. School of Life Science and Technology, Tongji University, 200092 Shanghai, China.
9. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02215, USA.
10. Stem Cell Program, Boston Children's Hospital, Boston, MA 02215, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
11. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
12. Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
13. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
14. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
15. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA 02115, USA.
16. Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Experimental Therapeutics Core, Dana-Farber Cancer Institute, Boston, MA 02210, USA.
17. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
18. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215, USA; Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, LC4114, Boston, MA 02215, USA. Electronic address: [email protected].

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.

Keywords

YAP; dormancy; drug resistance; drug tolerance; epidermal growth factor receptor; lung cancer; senescence.