PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers

Jin, Guang; Kim, Min Jung; Jeon, Hyo-Sung; Choi, Jin Eun; Kim, Dong Sun; Lee, Eung Bae; Ick, Sung; Yoon, Ghil Sook; Kim, Chang Ho; Jung, Tae Hoon; Park, Jae Yong

doi:10.1016/j.lungcan.2009.11.012

Cited by 153 publications

(132 citation statements)

References 23 publications

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“…This may be because there is a low-level copy-number gain of MET in a much higher percentage of the tumors, but the biologic implications are unclear. In lung cancer, the estimated frequency of mutations is low (1% for SCC (51,52,54) 3q26.3 33% 6% SOX2 amplification (23,24) 3q26.3-q27 23% Very rare FGFR1 amplification (24,25) 8p12 22% 1% PTEN mutation (36,61) 10q23.3 10% 2% MET amplification (34,35) 7q31.1 3%-21% 3%-21% PTEN loss (59,62) 10q23.3 8%-20% 8%-20% KRAS mutation (36) 12p12.1 6% 21% Variant III mutation (36) 7p12 5% Very rare LKB1 mutation (70) 19p13.3 5% 23% DDR2 mutation (30) 1q23.3 4% 1% HER2 overexpression (39)(40)(41)(42) 17q11.2-q12, 17q21 3%-5% 5%-9% PI3KCA mutation (50)(51)(52) 3q26.3 3% 3% BRAF mutation (36,64) 7p34 2% 1%-3% EGFR mutation (36) 7p12 <5% 10%-15% AKT1 mutation (56) 14q32.32 1% Very rare MET mutation (36) 7q31.1 1% 2% HER2 mutation (46,48,49) 17q11.2-q12, 17q21 1% 2% EML4-ALK fusion (66,67) 2p21, 2p23 1% 2%-7% and 2% for adenocarcinoma), and MET-mutated cells reveal enhanced ligand-mediated proliferation and significant in vivo tumor growth (36,37). Human EGF2 (ERBB2/Her2) is a transmembrane tyrosine kinase receptor that has no ligand-binding domain of its own.…”

Section: Translational Relevancementioning

confidence: 99%

“…PTEN inactivation occurs more frequently at the protein level than at the genomic level, and promoter methylation is found in 35% of PTEN-negative NSCLC (59,60). PTEN mutations have been described in 10% of lung SCC samples, compared with 2% of adenocarcinomas (36,61). At the genomic level, PTEN loss is seen in 8% to 20% of both histologic subtypes (59,62).…”

Section: Signaling Pathway Alterationsmentioning

confidence: 99%

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Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

Pérez-Moreno

Brambilla

Thomas

et al. 2012

Clinical Cancer Research

272

210

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Lung cancer is the leading cause of cancer-related deaths worldwide. Next to adenocarcinoma, squamous cell carcinoma (SCC) of the lung is the most frequent histologic subtype in non-small cell lung cancer. Encouraging new treatments (i.e., bevacizumab, EGFR tyrosine kinase inhibitors, and ALK inhibitors) have afforded benefits to patients with adenocarcinoma, but unfortunately the same is not true for SCC. However, many genomic abnormalities are present in SCC, and there is growing evidence of their biologic significance. Thus, in the short term, the molecular characterization of patients with SCC in modern profiling platforms will probably be as important as deciphering the molecular genetics of adenocarcinoma. Patients with SCC of the lung harboring specific molecular defects that are actionable (e.g., fibroblast growth factor receptor 1 amplification, discoidin domain receptor 2 mutation, and phosphoinositide 3-kinase amplification) should be enrolled in prospective clinical trials targeting such molecular defects.

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Section: Translational Relevancementioning

confidence: 99%

Section: Signaling Pathway Alterationsmentioning

confidence: 99%

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

Pérez-Moreno

Brambilla

Thomas

et al. 2012

Clinical Cancer Research

272

210

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“…The most common type of lung cancer (approximately 85%) is non-small cell lung cancer (NSCLC), which has three main types: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma (Molina et al, 2008;Shames and Wistuba, 2014). Genetic alterations in NSCLC tumors primarily include oncogenic mutations in the epidermal growth factor receptor (EGFR) and KRAS, as well as inactivation of tumor suppressor genes such as p53, PTEN, Rb, and p16 (Hollstein et al, 1991;Reissmann et al, 1993;Jin et al, 2010). Mutations in the EGFR gene, particularly deletion of exon 19 and L858R mutation in exon 21, occur in 10-50% of NSCLC patients (Gazdar, 2009;Cooper et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Protein Kinase CαMediates Erlotinib Resistance in Lung Cancer Cells

Abera

Kazanietz

2015

Mol Pharmacol

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Overexpression and mutational activation of the epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of non-small cell lung cancer (NSCLC). EGFR tyrosine-kinase inhibitors (TKIs) are given as a primary therapy for advanced patients with EGFR-activating mutations; however, the majority of these tumors relapse and patients eventually develop resistance to TKIs. To address a potential role of protein kinase C (PKC) isozymes in the resistance to TKIs, we used the isogenic NSCLC H1650 cell line and its erlotinib-resistant derivative H1650-M3, a cell line that displays a mesenchymallike morphology driven by transforming growth factor-b signaling. We found that H1650-M3 cells display remarkable PKCa upregulation and PKCd downregulation. Notably, silencing PKCa from H1650-M3 cells using RNA interference caused a significant reduction in the expression of epithelial-tomesenchymal transition (EMT) markers vimentin, Zeb2, Snail, and Twist. Moreover, pharmacological inhibition or PKCa RNA interference depletion and PKCd restoring sensitized H1650-M3 cells to erlotinib. Whereas ectopic overexpression of PKCa in parental H1650 cells was not sufficient to alter the expression of EMT genes or to confer resistance to erlotinib, it caused downregulation of PKCd expression, suggesting a unidirectional crosstalk. Finally, mechanistic studies revealed that PKCa upregulation in H1650-M3 cells is driven by transforming growth factor-b. Our results identified important roles for specific PKC isozymes in erlotinib resistance and EMT in lung cancer cells, and highlight PKCa as a potential target for lung cancer treatment.

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“…Mutations in PIK3CA are less common (3%-10% of SQCLC) and oncogenic alterations are frequently localized in exon 9 (E542K and E545K) and exon 20 (H1047R), which correspond to the helical domain and the kinase domain of p110a subunit, respectively (7,9,(11)(12)(13)(14)(15). PTEN loss and PTEN inactivating mutations are reported in 8% to 59% and 3% to 10% of SQCLC, respectively (7,9,10,(14)(15)(16)(17). AKT activating mutation is less frequent (1%-2%), whereas its overexpression involves 19% to 32% of SQCLC (6,9).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations

Bonelli

Cavazzoni

Saccani

et al. 2015

Molecular Cancer Therapeutics

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A prominent role in the pathogenesis of squamous cell carcinoma of the lung (SQCLC) has been attributed to the aberrant activation of the PI3K signaling pathway, due to amplification or mutations of the p110a subunit of class I phosphatidylinositol 3-kinase (PIK3CA) gene. The aim of our study was to determine whether different genetic alterations of PIK3CA affect the biologic properties of SQCLC and to evaluate the response to specific targeting agents in vitro and in vivo. The effects of NVP-BEZ235, NVP-BKM120, and NVP-BYL719 on two-dimensional/three-dimensional (2D/3D) cellular growth, epithelial-to-mesenchymal transition, and invasiveness were evaluated in E545K or H1047R PIK3CA-mutated SQCLC cells and in newly generated clones carrying PIK3CA alterations, as well as in a xenograft model. PIK3CA mutated/amplified cells showed increased growth rate and enhanced migration and invasiveness, associated with an increased activity of RhoA family proteins and the acquisition of a mesenchymal phenotype. PI3K inhibitors reverted this aggressive phenotype by reducing metalloproteinase production, RhoA activity, and the expression of mesenchymal markers, with the specific PI3K inhibitors NVP-BKM120 and NVP-BYL719 being more effective than the dual PI3K/mTOR inhibitor NVP-BEZ235. A xenograft model of SQCLC confirmed that PIK3CA mutation promotes the acquisition of a mesenchymal phenotype in vivo and proved the efficacy of its specific targeting drug NVP-BYL719 in reducing the growth and the expression of mesenchymal markers in xenotransplanted tumors. These data indicate that PIK3CA mutation/amplification may represent a good predictive feature for the clinical application of specific PI3K inhibitors in SQCLC patients.

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PTEN mutations and relationship to EGFR, ERBB2, KRAS, and TP53 mutations in non-small cell lung cancers

Cited by 153 publications

References 23 publications

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

Squamous Cell Carcinoma of the Lung: Molecular Subtypes and Therapeutic Opportunities

Protein Kinase CαMediates Erlotinib Resistance in Lung Cancer Cells

Inhibition of PI3K Pathway Reduces Invasiveness and Epithelial-to-Mesenchymal Transition in Squamous Lung Cancer Cell Lines Harboring PIK3CA Gene Alterations

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