PAK1 is a novel therapeutic target in tyrosine kinase inhibitor-resistant lung adenocarcinoma activated by the PI3K/AKT signaling regardless of EGFR mutation

De-Wei Wu, Tzu-Chin Wu, Chih-Yi Chen, Huei Lee

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

PPurpose: EGFR mutation as a biomarker has been documented that EGFR-mutant patients will derive clinical benefit from TKI treatment. Unfortunately, most patients show TKI resistance and tumor recurrence after therapy. Therefore, we expected that an adjuvant biomarker other than EGFR mutation is needed for predicting TKI resistance.

EXPERIMENTAL DESIGN: Molecular manipulations were performed to verify whether TKI resistance mediated by PAK1 could be through increasing Mcl-1 protein stability via the PI3K/AKT/C/EBP-β/miR-145 cascade. Xenograft mouse models were used to confirm the mechanistic action of PAK1 on TKI resistance. Forty-six tumor tissues from lung adenocarcinoma patients who received TKI therapy were collected to evaluate PAK1 and E-cadherin mRNA expressions by real-time PCR. The association of PAK1 and E-cadherin mRNA expressions with tumor response to TKI treatment and outcomes were evaluated.

RESULTS: We demonstrate that PAK1 confers TKI resistance in EGFR-mutant cells as well as in EGFR-wild-type cells. Mechanistically, the positive feedback loop of PAK1/PI3K/AKT/C/EBP-β /miR-145 cascades persistently activates the PI3K/AKT signaling pathway to protect Mcl-1 degradation by Fbw7, which results, in turn, in TKI resistance and cell invasion via epithelial-to-mesenchymal transition due to a decrease in E-cadherin expression. The mechanism underlying the cell model is further confirmed in xenograft tumors. Among patients, high-PAK1 or low-E-cadherin tumors more commonly exhibited an unfavorable response to TKI and poorer outcome compared with low-PAK1 or high-E-cadherin tumors.

CONCLUSIONS: The combination of TKI with AKT inhibitor might confer TKI sensitivity and in turn improve outcomes in lung adenocarcinoma patients who harbored high PAK1 mRNA expressing tumors.

Original languageEnglish
JournalClinical Cancer Research
DOIs
Publication statusPublished - May 13 2016

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