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Author Notes:

Shi-Yong Sun, Ph.D., Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, 1365-C Clifton Road, C3088, Atlanta, GA 30322. Phone: (404) 778-2170; Fax: (404) 778-5520; Email: ssun@emory.edu

ZC had initial conception, designed and conducted most experiments, collected and analyzed data, and drafted manuscript; KAV and HC contributed to some experiments and manuscript writing. JZ and SSR contributed to project discussion, funding acquisition and manuscript editing. SYS had initial conception, supervised and coordinated the study, participated in data analyses, contributed to funding acquisition and completed the final version of the manuscript.

Zhen Chen: Conceptualization, Investigation, Formal analysis, Data curation and Writing – Original Draft and Writing - Review & Editing. Karin A. Vallega: Investigation, Writing – Original Draft and Writing - Review & Editing. Haiying Chen: Investigation, Writing – Original Draft. Jia Zhou: Supervision, Writing – Original Draft. Suresh S. Ramalingam: Supervision, Writing – Original Draft and Funding acquisition. Shi-Yong Sun: Conceptualization, Supervision, Project administration, Writing – Original Draft, Writing - Review & Editing and Funding acquisition.

SSR is on consulting/advisory boards for AstraZeneca, BMS, Merck, Roche, Tesaro and Amgen. Other authors declare that they have no competing interests.

Subjects:

Research Funding:

This study was in part supported by the NIH/NCI R01 CA223220 (to SYS), R01 CA245386 (to SYS) and UG1 CA233259 (to SSR), Emory Winship Cancer Institute lung cancer research pilot funds (to SYS), and the John D. Stobo, M.D. Distinguished Chair Endowment Fund at UTMB (to JZ). SSR and SYS are Georgia Research Alliance Distinguished Cancer Scientists.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Pharmacology & Pharmacy
  • Berberine
  • EGFR
  • Osimertinib
  • Resistance
  • MET
  • Lung cancer
  • ACQUIRED-RESISTANCE
  • BREAST-CANCER
  • KINASE INHIBITORS
  • EGFR INHIBITORS
  • UP-REGULATION
  • CELLS
  • EXPRESSION
  • PROTEIN
  • GROWTH
  • AMPLIFICATION

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

Tools:

Journal Title:

PHARMACOLOGICAL RESEARCH

Volume:

Volume 175

Publisher:

, Pages 105998-105998

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Berberine is a natural product that has long been used in traditional Chinese medicine due to its antimicrobial, anti-inflammatory and metabolism-regulatory properties. Osimertinib is the first third-generation EGFR-tyrosine kinase inhibitor (TKI) approved for the treatment of non-small cell lung cancer (NSCLC) with activating EGFR mutations and those resistant to earlier generation EGFR-TKIs due to a T790M mutation. However, emergence of acquired resistance to osimertinib limits its long-term efficacy in the clinic. One known mechanism of acquired resistance to osimertinib and other EGFR-TKIs is MET (c-MET) gene amplification. Here, we report that berberine, when 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 enhanced suppressive effect on the growth of MET-amplified osimertinib-resistant xenografts in nude mice and was well tolerated. Molecular modeling showed that berberine was able to bind to the kinase domain of non-phosphorylated MET, occupy the front of the binding pocket, and interact with the activation loop, in a similar way as other known MET inhibitors do. MET kinase assay showed clear concentration-dependent inhibitory effects of berberine against MET activity, confirming its kinase inhibitory activity. 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.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/).
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