Targeting EGFR in non-small-cell lung cancer: Lessons, experiences, strategies

Stella, Giulia Maria; Luisetti, Maurizio; Inghilleri, Simona; Cemmi, Francesca; Scabini, Roberta; Zorzetto, Michele; Pozzi, Ernesto

doi:10.1016/j.rmed.2011.10.015

Cited by 66 publications

(46 citation statements)

References 134 publications

(107 reference statements)

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“…In lung adenocarcinoma, EGFR is overexpressed in more than 39% and has emerged as a leading target for the treatment of patients with adenocarcinoma (10)(11)(12). Some TKIs, like gefitinib, significantly improved survival and prognosis of patients with lung adenocarcinoma, while some patients acquired resistance after initial response to TKIs or even had intrinsic resistance without EGFR mutations (13).…”

Section: Introductionmentioning

confidence: 99%

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Zhou

Guo

et al. 2016

Molecular Cancer Research

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The epidermal growth factor receptor (EGFR) activates downstream mTOR phosphorylation to promote the progression of many different tumor types, thus making it a prime therapeutic target. However, the role of DEP domain-containing mTORinteracting protein (DEPTOR), a natural mTOR inhibitor, remains unclear in this process. Here, it is reported that EGFR expression is significantly increased in tumors of lung adenocarcinoma patients and is negatively correlated with the expression of DEPTOR. Activation of EGFR signaling, by EGF, in A549 lung adenocarcinoma cells (overexpressing EGFR) significantly enhanced the function of the mTOR autoamplification loop, consisting of S6K, mTOR, CK1a, and bTrCP1, which resulted in downregulation of DEPTOR expression. Gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of the mTOR autoamplification loop. Furthermore, a series of assays conducted in DEPTOR knockout or ectopic expression in A549 cells confirmed that DEPTOR inhibited proliferation, migration, and invasion as well as the in vivo tumor growth of lung adenocarcinoma. Importantly, tumor progression mediated by EGFR ectopic expression was diminished by transfection with DEPTOR. This study uncovers the important inhibitory role of DEPTOR in lung adenocarcinoma progression and reveals a novel mechanism that EGFR downregulates DEPTOR expression to facilitate tumor growth.Implications: DEPTOR acts as a tumor suppressor by limiting EGFR-driven lung adenocarcinoma progression.

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Section: Introductionmentioning

confidence: 99%

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Zhou

Guo

et al. 2016

Molecular Cancer Research

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“…The overall 5-year survival rate of lung cancer is as low as 15 % [1]. Lung cancer usually forms in the cells lining air passages.…”

Section: Introductionmentioning

confidence: 99%

A non-tight junction function of claudin-7—Interaction with integrin signaling in suppressing lung cancer cell proliferation and detachment

et al. 2015

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BackgroundClaudins are a family of tight junction (TJ) membrane proteins involved in a broad spectrum of human diseases including cancer. Claudin-7 is a unique TJ membrane protein in that it has a strong basolateral membrane distribution in epithelial cells and in tissues. Therefore, this study aims to investigate the functional significance of this non-TJ localization of claudin-7 in human lung cancer cells.MethodsClaudin-7 expression was suppressed or deleted by lentivirus shRNA or by targeted-gene deletion. Cell cycle analysis and antibody blocking methods were employed to assay cell proliferation and cell attachment, respectively. Electron microscopy and transepthelial electrical resistance measurement were performed to examine the TJ ultrastructure and barrier function. Co-immunolocalization and co-immunoprecipitation was used to study claudin-7 interaction with integrin β1. Tumor growth in vivo were analyzed using athymic nude mice.ResultsClaudin-7 co-localizes and forms a stable complex with integrin β1. Both suppressing claudin-7 expression by lentivirus shRNA in human lung cancer cells (KD cells) and deletion of claudin-7 in mouse lungs lead to the reduction in integrin β1 and phospho-FAK levels. Suppressing claudin-7 expression increases cell growth and cell cycle progression. More significantly, claudin-7 KD cells have severe defects in cell-matrix interactions and adhere poorly to culture plates with a remarkably reduced integrin β1 expression. When cultured on uncoated glass coverslips, claudin-7 KD cells grow on top of each other and form spheroids while the control cells adhere well and grow as a monolayer. Reintroducing claudin-7 reduces cell proliferation, upregulates integrin β1 expression and increases cell-matrix adhesion. Integrin β1 transfection partially rescues the cell attachment defect. When inoculated into nude mice, claudin-7 KD cells produced significantly larger tumors than control cells.ConclusionIn this study, we identified a previously unrecognized function of claudin-7 in regulating cell proliferation and maintaining epithelial cell attachment through engaging integrin β1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-015-0387-0) contains supplementary material, which is available to authorized users.

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“…These findings have subsequently translated into significant clinical advances due to the inclusion of molecularly targeted agents in novel therapeutic strategies for this disease (5). As an example, first-line therapy for NSCLCs has been revolutionized by agents that inhibit the EGF receptor (EGFR) in tumors that harbor activating mutations in this receptor tyrosine kinase, including the tyrosine kinase inhibitors (TKI) gefitinib and erlotinib (6). More recently, discovery of the anaplastic lymphoma kinase (ALK) gene rearrangement in a subset of patients with NSCLCs led to the rapid approval of the multitargeted TKI crizotinib as another genotype-driven therapy (7).…”

Section: Introductionmentioning

confidence: 99%

Targeting KRAS-Mutant Non–Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib

Acquaviva

Smith

Sang

et al. 2012

Molecular Cancer Therapeutics

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Mutant KRAS is a feature of more than 25% of non-small cell lung cancers (NSCLC) and represents one of the most prevalent oncogenic drivers in this disease. NSCLC tumors with oncogenic KRAS respond poorly to current therapies, necessitating the pursuit of new treatment strategies. Targeted inhibition of the molecular chaperone Hsp90 results in the coordinated blockade of multiple oncogenic signaling pathways in tumor cells and has thus emerged as an attractive avenue for therapeutic intervention in human malignancies. Here, we examined the activity of ganetespib, a small-molecule inhibitor of Hsp90 currently in clinical trials for NSCLCs in a panel of lung cancer cell lines harboring a diverse spectrum of KRAS mutations. In vitro, ganetespib was potently cytotoxic in all lines, with concomitant destabilization of KRAS signaling effectors. Combinations of low-dose ganetespib with MEK or PI3K/mTOR inhibitors resulted in superior cytotoxic activity than single agents alone in a subset of mutant KRAS cells, and the antitumor efficacy of ganetespib was potentiated by cotreatment with the PI3K/mTOR inhibitor BEZ235 in A549 xenografts in vivo. At the molecular level, ganetespib suppressed activating feedback signaling loops that occurred in response to MEK and PI3K/mTOR inhibition, although this activity was not the sole determinant of combinatorial benefit. In addition, ganetespib sensitized mutant KRAS NSCLC cells to standard-of-care chemotherapeutics of the antimitotic, topoisomerase inhibitor, and alkylating agent classes. Taken together, these data underscore the promise of ganetespib as a single-agent or combination treatment in KRAS-driven lung tumors. Mol Cancer Ther; 11(12); 2633-43. Ó2012 AACR.

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Targeting EGFR in non-small-cell lung cancer: Lessons, experiences, strategies

Cited by 66 publications

References 134 publications

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

A non-tight junction function of claudin-7—Interaction with integrin signaling in suppressing lung cancer cell proliferation and detachment

Targeting KRAS-Mutant Non–Small Cell Lung Cancer with the Hsp90 Inhibitor Ganetespib

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