The natural product berberine synergizes with osimertinib preferentially
against MET-amplified osimertinib-resistant lung cancer via MET
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.