PKM2/PDK1 dual-targeted shikonin derivatives restore the sensitivity of EGFR-mutated NSCLC cells to gefitinib by remodeling glucose metabolism

by Selleckchem | Jun 03 2023

Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis, but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity, we proposed a "two-step approach" that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC50 = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC50 = 4.56 μmol/L) and the positive control gefitinib (IC50 = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK. Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes, thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5, a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation.

Comments：

The statement discusses the role of two enzymes, pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1), in promoting tumor growth and drug resistance in non-small cell lung cancer (NSCLC) through accelerating aerobic glycolysis. The authors propose a "two-step approach" to target both enzymes simultaneously, using a combination of PKM2 activator and PDK1 inhibitor. Based on this, they designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 was found to be significantly more effective in inhibiting the proliferation of EGFR mutant NSCLC cell H1975, and also showed good anti-tumor activity in xenografted mouse models with lower toxicity side effects than SK. E5 was found to inhibit the entry of PKM2 into the nucleus, thus regulating the transcriptional activation of oncogenes and restoring the sensitivity of H1975 cell to gefitinib, a commonly used drug for EGFR-TKIs resistant NSCLC. The authors suggest that E5 could be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, and further investigation is warranted.