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Mol Cancer Res. 2017 Dec;15(12):1764-1776. doi: 10.1158/1541-7786.MCR-17-0298. Epub 2017 Aug 29.

A First-in-Class TWIST1 Inhibitor with Activity in Oncogene-Driven Lung Cancer.

Author information

1
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
2
Department of Medicine, Division of Hematology-Oncology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.
3
Department of Pharmacology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
4
Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
5
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
6
Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
7
Department of Neurological Surgery University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
8
Division of Pediatric Neurology, Oregon Health & Science University, Portland, Oregon.
9
Department of Medicine, Thoracic Oncology Service, Memorial Sloan Kettering Cancer Center, New York, New York.
10
Department of Urology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
11
Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania. burnstf@upmc.edu.

Abstract

TWIST1, an epithelial-mesenchymal transition (EMT) transcription factor, is critical for oncogene-driven non-small cell lung cancer (NSCLC) tumorigenesis. Given the potential of TWIST1 as a therapeutic target, a chemical-bioinformatic approach using connectivity mapping (CMAP) analysis was used to identify TWIST1 inhibitors. Characterization of the top ranked candidates from the unbiased screen revealed that harmine, a harmala alkaloid, inhibited multiple TWIST1 functions, including single-cell dissemination, suppression of normal branching in 3D epithelial culture, and proliferation of oncogene driver-defined NSCLC cells. Harmine treatment phenocopied genetic loss of TWIST1 by inducing oncogene-induced senescence or apoptosis. Mechanistic investigation revealed that harmine targeted the TWIST1 pathway through its promotion of TWIST1 protein degradation. As dimerization is critical for TWIST1 function and stability, the effect of harmine on specific TWIST1 dimers was examined. TWIST1 and its dimer partners, the E2A proteins, which were found to be required for TWIST1-mediated functions, regulated the stability of the other heterodimeric partner posttranslationally. Harmine preferentially promoted degradation of the TWIST1-E2A heterodimer compared with the TWIST-TWIST1 homodimer, and targeting the TWIST1-E2A heterodimer was required for harmine cytotoxicity. Finally, harmine had activity in both transgenic and patient-derived xenograft mouse models of KRAS-mutant NSCLC. These studies identified harmine as a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC including EGFR mutant, KRAS mutant and MET altered NSCLC.Implications: TWIST1 is required for oncogene-driven NSCLC tumorigenesis and EMT; thus, harmine and its analogues/derivatives represent a novel therapeutic strategy to treat oncogene-driven NSCLC as well as other solid tumor malignancies. Mol Cancer Res; 15(12); 1764-76. ©2017 AACR.

PMID:
28851812
PMCID:
PMC5712248
DOI:
10.1158/1541-7786.MCR-17-0298
[Indexed for MEDLINE]
Free PMC Article

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