Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases

Sun, Yihua; Ren, Yan; Fang, Zhaoyuan; Li, Chenguang; Fang, Rong; Gao, Bin; Han, Xiuxin; Tian, Weidong; Pao, William; Chen, Haiquan; Ji, Hongbin

doi:10.1200/jco.2010.29.6038

Cited by 308 publications

(282 citation statements)

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“…Detection of EGFR and KRAS mutations was previously described [18,21] . Briefly, genomic DNA and RNA were extracted from Chinese lung cancer cell lines per standard protocol (RNeasy Mini Kit, and QIAamp DNA Mini Kit, Qiagen, Hilden, Germany).…”

Section: Egfr and Kras Mutation Detectionmentioning

confidence: 99%

“…Studies demonstrate that ethnic differences in genetic background are important in defining cancer biology as well as in drug toxicity [14][15][16][17][18][19][20][21] . For example, the epidermal growth factor receptor (EGFR) kinase domain mutations occur in approximately 10% of NSCLC patients in the Caucasian popula tion [22] , but occur in 30%-50% of NSCLC patients from East Asian populations [15,17,18,21,23] .…”

Section: Introductionmentioning

confidence: 99%

“…For example, the epidermal growth factor receptor (EGFR) kinase domain mutations occur in approximately 10% of NSCLC patients in the Caucasian popula tion [22] , but occur in 30%-50% of NSCLC patients from East Asian populations [15,17,18,21,23] . Ethnic differences in the expression of allelic variants may produce altered pharmacokinetics and Establishment and characterization of primary lung cancer cell lines from Chinese population www.nature.com/aps Zheng C et al Acta Pharmacologica Sinica npg result in differential toxicity for the same anticancer treatments [19,20] .…”

Section: Introductionmentioning

confidence: 99%

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Establishment and characterization of primary lung cancer cell lines from Chinese population

Zheng

Sun

et al. 2011

Acta Pharmacol Sin

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Aim: To establish and characterize primary lung cancer cell lines from Chinese population. Methods: Lung cancer specimens or pleural effusions were collected from Chinese lung cancer patients and cultured in vitro with ACL4 medium (for non-small cell lung carcinomas (NSCLC)) or HITES medium (for small cell lung carcinomas (SCLC)) supplemented with 5% FBS. All cell lines were maintained in culture for more than 25 passages. Most of these cell lines were further analyzed for oncogenic mutations, karyotype, cell growth kinetics, and tumorigenicity in nude mice. Results: Eight primary cell lines from Chinese lung cancer patients were established and characterized, including seven NSCLC cell lines and one SCLC cell line. Five NSCLC cell lines were found to harbor epidermal growth factor receptor (EGFR) kinase domain mutations. Conclusion: These well-characterized primary lung cancer cell lines from Chinese population provide a unique platform for future studies of the ethnic differences in lung cancer biology and drug response.

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Section: Egfr and Kras Mutation Detectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Establishment and characterization of primary lung cancer cell lines from Chinese population

Zheng

Sun

et al. 2011

Acta Pharmacol Sin

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“…14 However, the known 'druggable' targets are primarily enriched in the subgroup of adenocarcinomas of never smokers. 15 In addition, molecularly targeted therapeutics such as erlotinib, gefitinib and cetuximab, as well as conventional chemotherapeutics such as pemetrexed are poorly active in squamous-cell lung cancer patients. 11,16 Drugs such as bevacizumab or sorafenib that primarily inhibit vascular endothelial growth factor receptor (VEGFR) signaling are also not registered for the treatment of squamous-cell lung cancer patients due to increased risk of fatal hemorrhage.…”

mentioning

confidence: 99%

Genetic insight and therapeutic targets in squamous-cell lung cancer

Sos

Thomas

2012

Oncogene

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Squamous-cell lung cancer is one of the most prevalent subtypes of lung cancer worldwide and its pathogenesis is closely linked with tobacco exposure. Unfortunately, squamous-cell lung cancer patients do not benefit from major advances in the development of targeted therapeutics such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors that show exquisite activity in lung adenocarcinomas with EGFR mutations or echinoderm microtubule associated protein like-4 (EML4)-ALK fusions, respectively. Major efforts have been launched to characterize the genomes of squamous-cell lung cancers. Among the new results emanating from these efforts are amplifications of the fibroblast growth factor receptor 1 gene and mutations of the discoidin domain receptor 2 gene as potential novel targets for the treatment of squamous-cell lung cancer patients. Here, we provide a review on these discoveries and their implications for clinical trials in squamous-cell lung cancer assessing the value of novel therapeutics addressing these targets.Oncogene ( Keywords: squamous-cell lung cancer; FGFR1; DDR2 Major advances in molecular biology and high-throughput sequencing techniques have boosted cancer drug treatment strategies over the past decades. 1 --6 The envisioned paradigm is the identification of genetic aberrations that are unique for defined subgroups of patients, and the development of drugs that specifically aim at oncogenic targets and their signaling pathways of these patients. In lung cancer, this development has led to the identification of oncogenic EGFR mutations that are present in up to 20% of adenocarcinoma patients 7 --9 and confer exquisite sensitivity to EGFR inhibitors (for example, gefitinib, erlotinib). 10 --12 Another example is the identification of EML4-ALK, the first fusion gene that is causally linked with the development of lung cancer. 13 Encouraging first clinical studies show that in patients with EML4 --ALK fusions overall response rates of up to 57% can be observed when treated with crizotinib. 14 However, the known 'druggable' targets are primarily enriched in the subgroup of adenocarcinomas of never smokers. 15 In addition, molecularly targeted therapeutics such as erlotinib, gefitinib and cetuximab, as well as conventional chemotherapeutics such as pemetrexed are poorly active in squamous-cell lung cancer patients. 11,16 Drugs such as bevacizumab or sorafenib that primarily inhibit vascular endothelial growth factor receptor (VEGFR) signaling are also not registered for the treatment of squamous-cell lung cancer patients due to increased risk of fatal hemorrhage. 17,18 Thus, the therapeutic repertoire for squamouscell lung cancer patients is rather limited.Several genomic studies tackled this unmet medical need by systematically characterizing the landscape of genetic lesions of squamous-cell lung cancer patients in order to define new therapeutically amenable targets. The first large-scale analysis of significant copy-number changes in squamous-cell lun...

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“…8,16 Both pathways may occur in former smokers whose lung cancer risk persists beyond 30 years of smoking cessation. 45 Lung cancer in nonsmokers and in patients with lung adenocarcinoma that is unrelated to active or second-hand smoke are associated with a higher frequency of EGFR mutation, 46,47 whereas lung cancer in former and/or current smokers demonstrates more frequent KRAS and p53 mutations. 48 Seemingly, the p120ctn/Cdc42/Rac1 pathway could be activated by constitutively active EGFR mutant in the absence of smoke exposure, eventually causing lung adenocarcinoma in patients who have never smoked.…”

Section: Rac1 Modulates Smoke-induced Migrationmentioning

confidence: 99%

Rac1 and Cdc42 Differentially Modulate Cigarette Smoke–Induced Airway Cell Migration through p120-Catenin–Dependent and –Independent Pathways

Zhang

Gallup

Zlock

et al. 2013

The American Journal of Pathology

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The adherens junction protein p120-catenin (p120ctn) shuttles between E-cadherinebound and cytoplasmic pools to regulate E-cadherin/catenin complex stability and cell migration, respectively. When released from the adherens junction, p120ctn promotes cell migration through modulation of the Rho GTPases Rac1, Cdc42, and RhoA. Accordingly, the down-regulation and cytoplasmic mislocalization of p120ctn has been reported in all subtypes of lung cancers and is associated with grave prognosis. Previously, we reported that cigarette smoke induced cytoplasmic translocation of p120ctn and cell migration, but the underlying mechanism was unclear. Using primary human bronchial epithelial cells exposed to smoke-concentrated medium (Smk), we observed the translocation of Rac1 and Cdc42, but not RhoA, to the leading edge of polarized and migrating human bronchial epithelial cells. Rac1 and Cdc42 were robustly activated by smoke, whereas RhoA was inhibited. Accordingly, siRNA knockdown of Rac1 or Cdc42 completely abolished Smk-induced cell migration, whereas knockdown of RhoA had no effect. p120ctn/Rac1 double knockdown completely abolished Smk-induced cell migration, whereas p120ctn/Cdc42 double knockdown did not. These data suggested that Rac1 and Cdc42 coactivation was essential to smoke-promoted cell migration in the presence of p120ctn, whereas migration proceeded via Rac1 alone in the absence of p120ctn. Thus, Rac1 may provide an omnipotent therapeutic target in reversing cell migration during the early (intact p120ctn) and late (loss of p120ctn) stages of lung carcinogenesis. (Am J Pathol 2013 http://dx.doi.org/10.1016/j.ajpath.2013 Cigarette smoke contains >4000 active constituents, !60 of which are established carcinogens and/or mutagens. 1 With a 20-fold greater risk of lung cancer and accounting for 87% of lung cancererelated deaths, 2 smoking continues to represent the single most important carcinogenic exposure. Because treatment of lung cancer is largely ineffective, recent research has been focused on efforts to identify and reverse early events leading to the initiation of lung cancer by smoke. 3 Emerging evidence suggests that smoke mediates epithelial-mesenchymal transition (EMT) and pretumor cell migration by disrupting cell-cell adhesion in polarized mucosal epithelia. 4,5 During EMT, cells switch from a polarized immobile epithelial phenotype to a highly motile fibroblast phenotype. 6 Unregulated EMT confers epithelial cells with stem cellelike properties capable of self-renewal, metastasis, and resistance to apoptosis. 6,7 Little is known about how smoke mediates EMT during the early stages of lung cancer.E-cadherin (E-cad)ebased adherens junctions (AJs) interact with catenins to modulate cell-cell adhesion. 8 Structural analysis by X-ray crystallography revealed that p120-catenin (p120ctn) binds to the juxtamembrane domain of E-cad, where it regulates stability and turnover of E-cad by concealing the juxtamembrane domain residues implicated in endocytosis and ubiquitination of E-cad. 9,10 The disruption ...

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Lung Adenocarcinoma From East Asian Never-Smokers Is a Disease Largely Defined by Targetable Oncogenic Mutant Kinases

Cited by 308 publications

References 32 publications

Establishment and characterization of primary lung cancer cell lines from Chinese population

Establishment and characterization of primary lung cancer cell lines from Chinese population

Genetic insight and therapeutic targets in squamous-cell lung cancer

Rac1 and Cdc42 Differentially Modulate Cigarette Smoke–Induced Airway Cell Migration through p120-Catenin–Dependent and –Independent Pathways

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