loading page

The natural product berberine synergizes with osimertinib preferentially against MET-amplified osimertinib-resistant lung cancer via MET inhibition
  • +2
  • Zhen Chen,
  • Karin Vallega,
  • Haiying Chen,
  • Jia Zhou,
  • Shi-Yong Sun
Zhen Chen
Emory University
Author Profile
Karin Vallega
Emory University
Author Profile
Haiying Chen
University of Texas Medical Branch at Galveston
Author Profile
Jia Zhou
University of Texas Medical Branch at Galveston
Author Profile
Shi-Yong Sun
Emory University

Corresponding Author:[email protected]

Author Profile

Abstract

Background and Purpose: Berberine is a natural antimicrobial, anti-inflammatory product used in traditional Chinese medicine. Osimertinib is the first third-generation EGFR-tyrosine kinase inhibitor (TKI) approved for non-small cell lung cancer (NSCLC) with activating EGFR mutations and those resistant to earlier generation EGFR-TKIs. However, emergence of acquired resistance limits its long-term efficacy. One known mechanism of acquired resistance to EGFR-TKIs is MET (c-MET) gene amplification. This study has demonstrated berberine’s potential in overcoming acquired resistance to osimertinib. Experimental Approach: Drug effects in vitro were evaluated through cell counts, colony formation, apoptosis and protein degradation assays, and gene overexpression/knockouts. In vivo drug effects were measured with mouse xenograft models. Berberine’s interactions with MET were determined via molecular docking analysis and protein kinase assays. Key Results: Berberine combined with osimertinib synergistically and selectively decreased the survival of several MET-amplified osimertinib-resistant EGFR mutant NSCLC cell lines with enhanced induction of apoptosis, likely through Bim elevation and Mcl-1 reduction. Importantly, this combination effectively suppressed the growth of MET-amplified osimertinib-resistant xenografts in nude mice and was well tolerated. Molecular modeling showed that berberine could bind to the kinase domain of non-phosphorylated MET, occupy the front of the binding pocket, and interact with the activation loop, similar to other known MET inhibitors. The MET kinase assay clearly showed berberine’s concentration-dependent inhibition of MET activity. Conclusions and Implications: These findings collectively suggest that berberine can act as a naturally-existing MET inhibitor to synergize with osimertinib in overcoming osimertinib acquired resistance caused by MET amplification.