A first-in-class twist1 inhibitor with activity in oncogene-driven lung cancer

Zachary A. Yochum, Jessica Cades, Lucia Mazzacurati, Neil M. Neumann, Susheel K. Khetarpal, Suman Chatterjee, Hailun Wang, Myriam A. Attar, Eric H.B. Huang, Sarah N. Chatley, Katriana Nugent, Ashwin Somasundaram, Johnathan A. Engh, Andrew J. Ewald, Yoon-Jae Cho, Charles M. Rudin, Phuoc T. Tran, Timothy F. Burns

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 driverdefined 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 firstin-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 oncogenedriven NSCLC as well as other solid tumor malignancies.

Original languageEnglish (US)
Pages (from-to)1764-1776
Number of pages13
JournalMolecular Cancer Research
Volume15
Issue number12
DOIs
StatePublished - Dec 1 2017

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Harmine
Oncogenes
Lung Neoplasms
Non-Small Cell Lung Carcinoma
Epithelial-Mesenchymal Transition
Twist-Related Protein 1
Carcinogenesis
Neoplasms
Dimerization
Computational Biology
Alkaloids
Heterografts
Proteolysis
Transcription Factors
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Yochum, Z. A., Cades, J., Mazzacurati, L., Neumann, N. M., Khetarpal, S. K., Chatterjee, S., ... Burns, T. F. (2017). A first-in-class twist1 inhibitor with activity in oncogene-driven lung cancer. Molecular Cancer Research, 15(12), 1764-1776. https://doi.org/10.1158/1541-7786.MCR-17-0298

A first-in-class twist1 inhibitor with activity in oncogene-driven lung cancer. / Yochum, Zachary A.; Cades, Jessica; Mazzacurati, Lucia; Neumann, Neil M.; Khetarpal, Susheel K.; Chatterjee, Suman; Wang, Hailun; Attar, Myriam A.; Huang, Eric H.B.; Chatley, Sarah N.; Nugent, Katriana; Somasundaram, Ashwin; Engh, Johnathan A.; Ewald, Andrew J.; Cho, Yoon-Jae; Rudin, Charles M.; Tran, Phuoc T.; Burns, Timothy F.

In: Molecular Cancer Research, Vol. 15, No. 12, 01.12.2017, p. 1764-1776.

Research output: Contribution to journalArticle

Yochum, ZA, Cades, J, Mazzacurati, L, Neumann, NM, Khetarpal, SK, Chatterjee, S, Wang, H, Attar, MA, Huang, EHB, Chatley, SN, Nugent, K, Somasundaram, A, Engh, JA, Ewald, AJ, Cho, Y-J, Rudin, CM, Tran, PT & Burns, TF 2017, 'A first-in-class twist1 inhibitor with activity in oncogene-driven lung cancer', Molecular Cancer Research, vol. 15, no. 12, pp. 1764-1776. https://doi.org/10.1158/1541-7786.MCR-17-0298
Yochum ZA, Cades J, Mazzacurati L, Neumann NM, Khetarpal SK, Chatterjee S et al. A first-in-class twist1 inhibitor with activity in oncogene-driven lung cancer. Molecular Cancer Research. 2017 Dec 1;15(12):1764-1776. https://doi.org/10.1158/1541-7786.MCR-17-0298
Yochum, Zachary A. ; Cades, Jessica ; Mazzacurati, Lucia ; Neumann, Neil M. ; Khetarpal, Susheel K. ; Chatterjee, Suman ; Wang, Hailun ; Attar, Myriam A. ; Huang, Eric H.B. ; Chatley, Sarah N. ; Nugent, Katriana ; Somasundaram, Ashwin ; Engh, Johnathan A. ; Ewald, Andrew J. ; Cho, Yoon-Jae ; Rudin, Charles M. ; Tran, Phuoc T. ; Burns, Timothy F. / A first-in-class twist1 inhibitor with activity in oncogene-driven lung cancer. In: Molecular Cancer Research. 2017 ; Vol. 15, No. 12. pp. 1764-1776.
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AU - Khetarpal, Susheel K.

AU - Chatterjee, Suman

AU - Wang, Hailun

AU - Attar, Myriam A.

AU - Huang, Eric H.B.

AU - Chatley, Sarah N.

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AU - Somasundaram, Ashwin

AU - Engh, Johnathan A.

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