Dual Targeting of EGFR with PLK1 Exerts Therapeutic Synergism in Taxane-Resistant Lung Adenocarcinoma by Suppressing ABC Transporters

Cancers

Yoosik Kim¹  Mark Borris D. Aldonza¹  Sol-Bi Shin²  Dae-Hoon Kim²  Da-Eun Kim²  Hyungshin Yim² 

[1] Department of Chemical and Biomolecular Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea;Department of Pharmacy, Institute of Pharmaceutical Science and Technology, College of Pharmacy, Hanyang University, Ansan 15588, Korea;

关键词: chemoresistance;    PLK1;    EGFR;    ABC transporter;    lung adenocarcinoma;   

DOI  :  10.3390/cancers13174413

来源: DOAJ

【 摘 要 】

To overcome the limitations of chemoresistance, combination therapies using druggable targets have been investigated. Our previous studies led us to hypothesize that the downregulation of PLK1 expression or activity can be one strategy to overcome the hurdles of taxane resistance by the downregulation of ABC transporters. To explore this, various versions of PLK1 including a constitutively active version, kinase-dead form, and polo-box domain mutant were expressed in paclitaxel-resistant lung adenocarcinoma (LUAD^TXR). Targeting PLK1 using shRNA or non-functional mutants downregulated ABCB1, ABCC9, and ABCG2 in LUAD^TXR cells, which was similar to the downregulation effects from treatment with PLK1 inhibitors. The high expression of EGFR in LUAD led us to administer gefitinib, showing a markedly reduced EGFR level in LUAD^TXR cells. When gefitinib and PLK1 inhibitors were combined, LUAD^TXR cells tended to undergo apoptosis more effectively than parental cells, showing a synergistic effect on the downregulation of ABC transporters through c-Myc and AP-1. Clinical data provide evidence for the relevance between survival rates and expressions of PLK1 and EGFR in LUAD patients. Based on these results, we suggest that a combination of gefitinib and PLK1 inhibitors exerts strong synergism in LUAD^TXR, which helps to overcome the limitations associated with taxanes.

【 授权许可】

Unknown