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

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• TWIST1 is a crucial transcription factor driving epithelial-mesenchymal transition (EMT) and tumorigenesis in oncogene-driven non-small cell lung cancer (NSCLC).
• Targeting TWIST1 presents a potential therapeutic strategy for NSCLC, necessitating the identification of effective inhibitors.

Purpose of the Study:

• To identify and characterize novel TWIST1 inhibitors using a chemical-bioinformatic approach.
• To evaluate the anti-tumor activity and mechanism of action of identified inhibitors in preclinical models of NSCLC.

Main Methods:

• Connectivity Mapping (CMAP) analysis was employed to screen for potential TWIST1 inhibitors.
• In vitro assays assessed the effects of identified compounds on TWIST1 functions, cell proliferation, senescence, and apoptosis.
• Mechanistic studies investigated TWIST1 protein degradation, dimerization, and the role of TWIST1-E2A heterodimers.
• In vivo efficacy was evaluated in transgenic and patient-derived xenograft mouse models of KRAS-mutant NSCLC.

Main Results:

• Harmine, a harmala alkaloid, was identified as a potent TWIST1 inhibitor, suppressing NSCLC cell dissemination, proliferation, and branching.
• Harmine treatment induced senescence or apoptosis, phenocopying genetic TWIST1 loss, and promoted TWIST1 protein degradation.
• Harmine preferentially induced degradation of the TWIST1-E2A heterodimer, which was essential for its cytotoxic effects.
• Harmine demonstrated significant anti-tumor activity in preclinical models of EGFR, KRAS, and MET-altered NSCLC.

Conclusions:

• Harmine is a first-in-class TWIST1 inhibitor with marked anti-tumor activity in oncogene-driven NSCLC.
• Targeting the TWIST1-E2A heterodimer is a critical mechanism for harmine's efficacy.
• Harmine and its derivatives represent a promising therapeutic strategy for NSCLC and other solid tumors driven by oncogenes.