Natural product discovery and development for targeting pyruvate dehydrogenase kinase 1 in EGFR-mutant NSCLC

Natural products have diverse bioactive molecules with high therapeutic potential, better biocompatibility, and lower toxicity than synthetic compounds. Pyruvate dehydrogenase kinase 1 (PDK1) inhibitors, such as dichloroacetate (DCA), increase energy production and have potential therapeutic applications in cancer and metabolic disorders. Combining DCA with EGFR-TKIs overcomes EGFR-TKI resistance.

This study aimed to identify a most selective and potent PDK inhibitor from natural products and to overcome EGFR-TKI resistance.

We found that several natural product compounds, such as hemistepsin A, huzhangoside A, ilimaquinone, otobaphenol and leemanine, exhibited inhibitory effects against PDK1 activity. Through experiments with cell lines transfected with the always inactive form of PDHA1, we found that leelamine, derived from the nodal bark of pine trees, is the most effective and selective PDK1 inhibitor we have identified. Leelamine and the established PDK inhibitor, DCA, were found to enhance the sensitivity of NSCLC cells with the EGFR-TKI, such as gefitinib and osimertinib, in the cells expressing the resisting-mutant form of EGFR. The combination of PDK inhibitors and EGFR-TKI overcome the resistance to EGFR-TKI mediated by the EGFR mutation in both in vitro and in vivo experiments.

This study demonstrates the potential of natural products as a source of PDK inhibitors. The combination of PDK inhibitors with EGFR-TKIs could provide a promising therapeutic option for patients with EGFR-mutant NSCLC. These findings provide insights for further investigation and development of PDK inhibitors from natural products as a targeted therapy for cancer treatment.

 

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Conflict of Interest

The authors declare no conflict of interest.

Publikationsverlauf

Artikel online veröffentlicht:
16. November 2023