Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling

Kanda, Rina; Kawahara, Akihiko; Watari, Kosuke; Murakami, Yûichi; Sonoda, Kahori; Maeda, Masashi; Fujita, Hideaki; Kage, Masayoshi; Uramoto, Hidetaka; Costa, Carlota; Kuwano, Michihiko; Ono, Masahiro

doi:10.1158/0008-5472.can-12-4502

Cited by 120 publications

(103 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our findings indicated that changes in Cdc42 activity, which is a Rho GTPase, and AKT were related to the modulation of integrinβ1 expression in DR-PDAC cells. A role for integrinβ1 in Rho GTPases and AKT activity was demonstrated in ovarian and lung cancer, respectively [38,39]. Therefore, our result combined with the current record [38][39][40] and supports integrinβ1 as the upstream factor in the regulation of Cdc42 and AKT activities during the acquisition of a DR phenotype in PDAC cells.…”

Section: Discussionsupporting

confidence: 79%

“…A role for integrinβ1 in Rho GTPases and AKT activity was demonstrated in ovarian and lung cancer, respectively [38,39]. Therefore, our result combined with the current record [38][39][40] and supports integrinβ1 as the upstream factor in the regulation of Cdc42 and AKT activities during the acquisition of a DR phenotype in PDAC cells. We demonstrated that high integrinβ1 expression accounted for the inherent and acquired resistance to genotoxic drugs because GR-PDAC cells with integrinβ1 suppression became sensitive to gemcitabine similar to PCL cells, and resistance to gemcitabine was impaired as integrinβ1 levels decreased in GR-pPDAC cells.…”

Section: Discussionsupporting

confidence: 79%

See 1 more Smart Citation

Integrinβ1 modulates tumour resistance to gemcitabine and serves as an independent prognostic factor in pancreatic adenocarcinomas

Yang

Shi

et al. 2016

Tumor Biol.

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies because of its broad resistance to chemotherapy. Numerous evidence indicates that integrinβ1 is upregulated in some human cancers, and it is correlated with resistance to various therapies. However, the role of integrinβ1 in chemotherapy is not clear in pancreatic cancer. The present study evaluates the potential of integrinβ1 to predict chemoresistance and prognosis in patients and to modulate resistance to gemcitabine in PDAC cells. Primary drug-resistance (DR) cancer cells were isolated, and DR cells from MiaPaCa-2 and AsPC-1 parent cell lines (PCL) were selected. Integrinβ1 expression was determined using immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and Western blotting. Changes in drug response after knockdown of integrinβ1 via RNA interference (RNAi) were evaluated using the viability of cancer cells as colon formation, proliferation using Western blot of Ki-67 and apoptosis using cleaved caspase-3 immunofluorescence. qRT-PCR and Western blot also detected variations in the activities of cdc42 and AKT after integrinβ1 suppression. Patient survival and relative factors were assessed using Kaplan-Meier and Cox regression analyses. Integrinβ1 expression was upregulated in PDAC, which was significantly associated with intrinsic and acquired gemcitabine resistance and worse outcomes. The downregulation of integrinβ1 attenuated PDAC chemoresistance, and this attenuation partially correlated with reduced Cdc42 and AKT activity, which are target molecules of integrinβ1 in some human cancers. These findings identified integrinβ1 as a special marker of drug resistance and a serious prognosis, and they furthermore support the use of integrinβ1 as a novel potential therapeutic target to overcome chemotherapy resistance. The results also suggest a possible drug-resistant signalling pathway of integrinβ1 in PDAC.

show abstract

Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 79%

Integrinβ1 modulates tumour resistance to gemcitabine and serves as an independent prognostic factor in pancreatic adenocarcinomas

Yang

Shi

et al. 2016

Tumor Biol.

View full text Add to dashboard Cite

show abstract

“…Integrin β1-silencing in A549 cells causes a defective activation of the EGFR signaling cascade, leading to impaired cell proliferation, migration and invasive behavior in vitro. Integrin β1 overexpression in lung cancer cells also has a key role in chemoresistance (38,39). In the present study, in the A549 cells, maspin negatively regulated the integrin β1 expression.…”

Section: Discussionsupporting

confidence: 55%

Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines

Zhou

Qin

Zhou

et al. 2015

International Journal of Molecular Medicine

View full text Add to dashboard Cite

Abstract. Mammary serine protease inhibitor (maspin) is a tumor suppressor gene that is silenced in the majority of cancer cells during metastatic progression by transcriptional and epigenetic mechanisms. The function of maspin in non-small cell lung cancer cells (NSCLC) has not been clearly defined. In the present study, the expression of maspin in NSCLC cell lines, in particular, the adenocarcinoma cell lines, was heterogeneous. While the expression levels of maspin in PC-9 and H460 cell lines were intact, the expression of maspin in the A549 and SPC-A1 cells was hardly detected. Ectopic expression of maspin in A549 cells carrying the K-ras gene point mutation significantly inhibited cell migration and invasion abilities, which was associated with downregulated expression of matrix metalloproteinase-2 and integrin β1. Ectopic expression of maspin in SPC-A1 cells harboring the wild-type K-ras gene predominantly affected cell growth via targeting the AKT signaling molecules. Maspin functions differently in lung adenocarcinoma cells, possibly due to the varied molecular characteristics. IntroductionLung cancer is a leading cause of cancer mortality worldwide. Lung cancer is generally divided into non-small cell lung cancer cells (NSCLC) and SCLC, in which the NSCLC constitutes 80-85% of lung cancers. The three major NSCLC subtypes are adenocarcinoma, squamous cell carcinoma and large cell carcinoma. NSCLC, which is characterized by slow tumor cell growth and dissemination, is refractory to chemotherapy and chest radiotherapy. Several driven genes have been identified in NSCLC, such as EGFR, c-MET and the ALK-EML4 fusion gene (1). Treatment for lung cancer is mainly based on tumor stage, tumor pathology and molecular pathology. Understanding thoroughly the molecular mechanism underlying the aberrant cellular events driving lung cancer progressions is crucial for developing novel treatments.Mammary serine protease inhibitor (maspin), also known as Serpin B5, was first identified in 1994 (2). Maspin belongs to the serine protease inhibitor superfamily, and is predominantly localized in the cytoplasm, but is also localized in the nucleus and membrane, and is secreted. The exact roles of maspin in cancer are far more complicated than initially thought due to the conflicting experimental and clinical data that have been reported. In prostate cancer, the expression of maspin is frequently absent (3). Overexpression of maspin is considered an independent factor in predicting a favorable prognosis in breast cancer and lung squamous cell cancer (4-6). However, it has been also reported that the increased nuclear maspin expression predicts a favorable prognosis, whereas the enhanced cytoplasmic expression is associated with early-relapsing and unfavorable prognosis in breast cancer (7). Enhanced expression of maspin is correlated with unfavorable prognosis in pancreatic, ovarian and colorectal cancer (8-10). High maspin expression correlates with an unfavorable outcome in colorectal cancer in stage III and IV, suggesting th...

show abstract

“…Src family kinase activation has been observed in cetuximab-resistant colorectal adenocarcinoma and NSCLC squamous cell carcinoma in vitro models (29,30), and it has been reported that CRIPTO1-mediated EGFR TKI resistance in NSCLC is Src-dependent (31). Furthermore, a recent report described increased expression and activation of Src, mediated by integrin activation, in EGFR TKI-resistant lung adenocarcinoma models (32). The present study extends these findings to demonstrate that overexpression of SRC is itself sufficient to bypass EGFR dependence in EGFR-dependent NSCLC, and that this function is shared by seven of the nine family members.…”

Section: Discussionmentioning

confidence: 97%

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Sharifnia

Rusu

Piccioni

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFRdependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFRindependent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival. epidermal growth factor receptor | non-small cell lung cancer | ORF

show abstract

Erlotinib Resistance in Lung Cancer Cells Mediated by Integrin β1/Src/Akt-Driven Bypass Signaling

Cited by 120 publications

References 40 publications

Integrinβ1 modulates tumour resistance to gemcitabine and serves as an independent prognostic factor in pancreatic adenocarcinomas

Integrinβ1 modulates tumour resistance to gemcitabine and serves as an independent prognostic factor in pancreatic adenocarcinomas

Different maspin functions in the lung adenocarcinoma A549 and SPC-A1 cell lines

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Contact Info

Product

Resources

About