Dataset Information

High PHLPP1 expression levels predicts longer time of acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma.

ABSTRACT:

Background

In spite of an initial good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in lung adenocarcinoma patients, resistance to treatment eventually occurs. Epidermal growth factor receptor (EGFR) activation stimulates Ras/Raf/Erk/MAPK and influences PI3K/Akt pathways, respectively. PHLPP negatively regulates PI3K/Akt and the RAF/RAS/ERK signaling pathways. Our study aimed to investigate the association between PH domain leucine-rich-repeats protein phosphatase (PHLPP) expression levels and the acquired resistance to EGFR TKIs in lung adenocarcinoma.

Results

High expression levels of PHLPP1 and PHLPP2 were detected in 69.3% and 61.3%, respectively, of patients with lung adenocarcinoma. Patients with high expression levels of PHLPP1 showed significantly longer median progression-free survival and overall survival than those with low expression levels of PHLPP1 (29 months versus 11 months, and 36 months versus 19 months respectively) (p = 0.0050 and p = 0.0052). PHLPP1, but not PHLPP2, protein expression levels was negatively correlated with p-Akt (473) and p-Erk1/2. The PHLPP1 expression levels were correlated with Progression-free survival and overall survival (p = 0.001 and p = 0.000).

Materials and methods

We recruited 75 patients with advanced lung adenocarcinoma receiving EGFR TKIs treatment. The expression levels of PHLPP1, PHLPP2, p-AKT(S473) and p-ERK1/2 were assessed using tissue immunostaining. The association of PHLPP expression levels with clinicopathological parameters and disease prognosis was analyzed.

Conclusions

This study suggests that high expression levels of PHLPP1 predict a better survival from target therapy and a longer time of acquired resistance to EGFR TKIs in patients with lung adenocarcinoma.

SUBMITTER: Xie Y

PROVIDER: S-EPMC5601709 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

High PHLPP1 expression levels predicts longer time of acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma.

Xie Youyou Y Lv Dongqing D Wang Wei W Ye Minhua M Chen Xiaofeng X Yang Haihua H

Oncotarget 20170801 35

<h4>Background</h4>In spite of an initial good response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in lung adenocarcinoma patients, resistance to treatment eventually occurs. Epidermal growth factor receptor (EGFR) activation stimulates Ras/Raf/Erk/MAPK and influences PI3K/Akt pathways, respectively. PHLPP negatively regulates PI3K/Akt and the RAF/RAS/ERK signaling pathways. Our study aimed to investigate the association between PH domain leucine-rich-repeats prot ...[more]

PMID: 28938613

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Project description:IntroductionEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are associated with favorable response in EGFR mutant lung cancer. Acquired resistance to reversible EGFR TKIs remains a significant barrier, and acquired EGFR T790M-mutation is the major mechanism. Second-generation irreversible EGFR TKI, afatinib, had also been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.ResultsForty-two patients had tissue specimens taken after acquiring resistance to afatinib. The sensitizing EGFR mutation were all consistent between pre- and post-afatinib tissues. Twenty patients (47.6%) had acquired T790M mutation. T790M rate was not different between first-generation EGFR TKI-naïve patients (50%) and first-generation EGFR TKI-treated patients (46.4%) (p = 0.827). No clinical characteristics or EGFR mutation types were associated with the development of acquired T790M. No other second-site EGFR mutations were detected. There were no small cell or squamous cell lung cancer transformation. Other genetic mutations were not identified in PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2.MethodsAfatinib-prescription record of our department of pharmacy from January 2007 and December 2014 was retrieved. We investigated patients with tissue specimens available after acquiring resistance to afatinib. Enrolled patients should have partial response or durable stable disease of treatment response to afatinib. Various mechanisms of acquired resistance to first-generation EGFR TKIs were evaluated. Histology and cytology were reviewed. EGFR, PIK3CA, BRAF, HER2, KRAS, NRAS, MEK1, AKT2, LKB1 and JAK2 genetic alterations were evaluated by sequencing. Statistical analysis was performed using Chi-square test and Kaplan-Meier method.ConclusionsT790M was detected in half of the lung adenocarcinoma after acquiring resistance to afatinib. T790M is still the major acquired resistance mechanism. First-generation EGFR TKI exposure did not influence the prevalence of T790M in lung cancer acquired resistance to afatinib.

Dataset Information

High PHLPP1 expression levels predicts longer time of acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma.

Background

Results

Materials and methods

Conclusions

Publications

High PHLPP1 expression levels predicts longer time of acquired resistance to EGFR tyrosine kinase inhibitors in patients with lung adenocarcinoma.

Similar Datasets

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