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Study of molecular mechanisms of sen...

Zhang, Zhenfeng.

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Study of molecular mechanisms of sensitivity and resistance to EGFR-targeted therapy in lung cancer.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Study of molecular mechanisms of sensitivity and resistance to EGFR-targeted therapy in lung cancer./
Author:	Zhang, Zhenfeng.
Description:	143 p.
Notes:	Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: .
Contained By:	Dissertation Abstracts International72-04B.
Subject:	Health Sciences, Pathology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3446483
ISBN:	9781124506036

Study of molecular mechanisms of sensitivity and resistance to EGFR-targeted therapy in lung cancer.
Zhang, Zhenfeng.

Study of molecular mechanisms of sensitivity and resistance to EGFR-targeted therapy in lung cancer. - 143 p.

Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: .

Thesis (Ph.D.)--Case Western Reserve University, 2011.

Lung cancer is still the leading cause of cancer-related death worldwide. EGFR-targeted tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, have dramatic clinical effects on EGFR-dependent lung cancers and are used as first-line therapy for patients with EGFR-mutant lung tumors. However, eventually all tumors acquire secondary resistance to the drugs and progress. Sensitivity to such EGFR-TKI is determined by activating mutations in EGFR tyrosine kinase domain whereas resistance to the TKI can be conferred by EGFR secondary mutations such as EGFR T790M and MET activation. Using a T790M-mutant H1975 NSCLC cell line which is gefitinib-resistant but sensitive to an irreversible EGFR inhibitor CL-387,785 allowed us to compare the target gene changes by treatment with gefitinib or CL387,785 in a transcriptional profiling study. We identified several dual specificity phosphatases (DUSPs) among the most highly and immediately regulated genes upon EGFR inhibition. DUSPs act as natural terminators of MAPK signal transduction and we demonstrate a tumor suppressive role of DUSP6 via targeting ERK activity. We also show that the regulation of DUSP6 is mediated at the promoter level by ETS1, a well-known nuclear target of activated ERK, indicating an important negative feedback loop in NSCLC. Furthermore, we developed an erlotinib-resistant NSCLC cell model and explored mechanisms of such resistance. We discover a novel mechanism of erlotinib resistance involving overexpression of AXL. Further studies confirm that co-treatment using erlotinib along with AXL knockdown or pharmacological inhibition resensitizes these resistant cells leading to cell death. These results suggest that an oncogenic switch from EGFR-dependent to EGFR/AXL-codependent signaling can lead to secondary EGFR-TKI resistance in NSCLC. In summary, our findings provide novel options for the improved targeting of EGFR-dependent tumors by the identification of DUSP6 and AXL as important modulators of EGFR sensitivity/resistance.

ISBN: 9781124506036Subjects--Topical Terms:

1017854
Health Sciences, Pathology.

Study of molecular mechanisms of sensitivity and resistance to EGFR-targeted therapy in lung cancer.
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245 1 0 $a Study of molecular mechanisms of sensitivity and resistance to EGFR-targeted therapy in lung cancer.
300 $a 143 p.
500 $a Source: Dissertation Abstracts International, Volume: 72-04, Section: B, page: .
500 $a Adviser: Balazs Halmos.
502 $a Thesis (Ph.D.)--Case Western Reserve University, 2011.
520 $a Lung cancer is still the leading cause of cancer-related death worldwide. EGFR-targeted tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, have dramatic clinical effects on EGFR-dependent lung cancers and are used as first-line therapy for patients with EGFR-mutant lung tumors. However, eventually all tumors acquire secondary resistance to the drugs and progress. Sensitivity to such EGFR-TKI is determined by activating mutations in EGFR tyrosine kinase domain whereas resistance to the TKI can be conferred by EGFR secondary mutations such as EGFR T790M and MET activation. Using a T790M-mutant H1975 NSCLC cell line which is gefitinib-resistant but sensitive to an irreversible EGFR inhibitor CL-387,785 allowed us to compare the target gene changes by treatment with gefitinib or CL387,785 in a transcriptional profiling study. We identified several dual specificity phosphatases (DUSPs) among the most highly and immediately regulated genes upon EGFR inhibition. DUSPs act as natural terminators of MAPK signal transduction and we demonstrate a tumor suppressive role of DUSP6 via targeting ERK activity. We also show that the regulation of DUSP6 is mediated at the promoter level by ETS1, a well-known nuclear target of activated ERK, indicating an important negative feedback loop in NSCLC. Furthermore, we developed an erlotinib-resistant NSCLC cell model and explored mechanisms of such resistance. We discover a novel mechanism of erlotinib resistance involving overexpression of AXL. Further studies confirm that co-treatment using erlotinib along with AXL knockdown or pharmacological inhibition resensitizes these resistant cells leading to cell death. These results suggest that an oncogenic switch from EGFR-dependent to EGFR/AXL-codependent signaling can lead to secondary EGFR-TKI resistance in NSCLC. In summary, our findings provide novel options for the improved targeting of EGFR-dependent tumors by the identification of DUSP6 and AXL as important modulators of EGFR sensitivity/resistance.
590 $a School code: 0042.
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