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

doi:10.1158/1078-0432.CCR-15-2724

中山醫學大學機構典藏 CSMUIR > 醫學院 > 醫學系 > 期刊論文 > Item 310902500/18174

Please use this identifier to cite or link to this item: https://ir.csmu.edu.tw:8080/ir/handle/310902500/18174

Title:	PAK1 is a novel therapeutic target in tyrosine kinase inhibitor-resistant lung adenocarcinoma activated by the PI3K/AKT signaling regardless of EGFR mutation
Authors:	Wu, D.-W.;Wu, T.-C.;Chen, Chen C.-Y.;Lee, H.
Date:	2016
Issue Date:	2017-08-08T09:48:34Z (UTC)
Publisher:	American Association for Cancer Research Inc.
ISSN:	10780432
Abstract:	Purpose: EGFR mutation as a biomarker has documented that EGFR-mutant patients will derive clinical benefit from tyrosine kinase inhibitor (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 p21-activated kinase (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 patients with lung adenocarcinoma who received TKI therapy were collected to evaluate PAK1 and E-cadherinm RNA expressions by real-time PCR. The association of PAK1 and E-cadherinmRNA expressions with tumor response to TKI treatment and outcomes was 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 low-Ecadherin tumors. Conclusions: The combination of TKI with AKT inhibitor might confer TKI sensitivity and in turn improve outcomes in patients with lung adenocarcinoma who harbored high PAK1 mRNA-expressing tumors. © 2016 American Association for Cancer Research.
URI:	http://dx.doi.org/10.1158/1078-0432.CCR-15-2724 https://www.scopus.com/inward/record.uri?eid=2-s2.0-84994654364&doi=10.1158%2f1078-0432.CCR-15-2724&partnerID=40&md5=07969b2739e3f40d2cf811a3b44cb427 https://ir.csmu.edu.tw:8080/ir/handle/310902500/18174
Relation:	Clinical Cancer Research 22(21) ,5370-5382
Appears in Collections:	[醫學系] 期刊論文

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