Gefitinib Induces Apoptosis in the EGFRL858R Non–Small-Cell Lung Cancer Cell Line H3255

Tracy, Sean I.; Mukohara, Toru; Hansen, Mark Berner; Meyerson, Matthew; Johnson, Bruce E.

doi:10.1158/0008-5472.can-04-1905

Cited by 331 publications

(291 citation statements)

References 19 publications

Supporting

Mentioning

253

Contrasting

Unclassified

Order By: Relevance

“…Our calculated responses for ERK and Akt signaling for normal EGFR expression agree with the qualitative experimental observations of Sordella et al 61 and Tracy et al: 65 namely, that the ERk stimulation levels decrease and the Akt levels are maintained for the mutant cells with normal EGFR expression levels. This preferential activation of Akt in L834R mutant cell lines observed in these experiments is consistent with the systems level predictions from our simulations.…”

Section: Discussionsupporting

confidence: 88%

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

et al. 2007

View full text Add to dashboard Cite

Abstract-We describe a hierarchical multiscale computational approach based on molecular dynamics simulations, free energy-based molecular docking simulations, deterministic network-based kinetic modeling, and hybrid discrete/ continuum stochastic dynamics protocols to study the dimermediated receptor activation characteristics of the Erb family receptors, specifically the epidermal growth factor receptor (EGFR). Through these modeling approaches, we are able to extend the prior modeling of EGF-mediated signal transduction by considering specific EGFR tyrosine kinase (EGFRTK) docking interactions mediated by differential binding and phosphorylation of different C-terminal peptide tyrosines on the RTK tail. By modeling signal flows through branching pathways of the EGFRTK resolved on a molecular basis, we are able to transcribe the effects of molecular alterations in the receptor (e.g., mutant forms of the receptor) to differing kinetic behavior and downstream signaling response. Our molecular dynamics simulations show that the drug sensitizing mutation (L834R) of EGFR stabilizes the active conformation to make the system constitutively active. Docking simulations show preferential characteristics (for wildtype vs. mutant receptors) in inhibitor binding as well as preferential enhancement of phosphorylation of particular substrate tyrosines over others. We find that in comparison to the wildtype system, the L834R mutant RTK preferentially binds the inhibitor erlotinib, as well as preferentially phosphorylates the substrate tyrosine Y1068 but not Y1173. We predict that these molecular level changes result in preferential activation of the Akt signaling pathway in comparison to the Erk signaling pathway for cells with normal EGFR expression. For cells with EGFR over expression, the mutant over activates both Erk and Akt pathways, in comparison to wildtype. These results are consistent with qualitative experimental measurements reported in the literature. We discuss these consequences in light of how the network topology and signaling characteristics of altered (mutant) cell lines are shaped differently in relationship to native cell lines.

show abstract

Section: Discussionsupporting

confidence: 88%

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

et al. 2007

View full text Add to dashboard Cite

show abstract

“…These experiments revealed that, in H441 cells, the dominant RTK activity was for EGFR, Her2, Her3 and Met receptors. The H441 cell line has been previously shown to be resistant to gefitinib and cetuximab (Tracy et al, 2004;Mukohara et al, 2005). We found that the activity of EGFR in these cells can be inhibited by the dual EGFR and Her2 kinase inhibitor GW2974 at high micromolar concentrations, which also affects the phosphorylation of Stat3, Akt and Shc, but not Erk1/2.…”

Section: Discussionmentioning

confidence: 81%

Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells

et al. 2009

View full text Add to dashboard Cite

There is a pressing need to identify new drug targets and novel approaches for treatment of non-small-cell lung carcinoma (NSCLC). Members of the epidermal growth factor receptor (EGFR) and Met receptor families have been identified as important molecular targets for NSCLC. Two EGFR tyrosine kinase inhibitors (TKIs; erlotinib and gefitinib) are in current clinical use, but a majority of patients do not respond to these targeted therapies. We used receptor TK (RTK) capture arrays to identify receptors active in NSCLC cell lines. As Met and ErbBs were active, we explored the potential therapeutic advantage of combined targeting of Met with ErbB receptor family inhibitors for treatment of NSCLC. We found that Met physically interacts with both EGFR and Her2 in a NSCLC cell line with overexpression/overactivation of Met. Combined use of a dual EGFR/Her2 inhibitor with a Met inhibitor yields maximal growth inhibition compared with the use of EGFR and/or Met inhibitors. This suggests that simultaneous inhibition of multiple RTKs may be needed to effectively abrogate tumour cell growth. Phosphoproteomic analysis by RTK capture arrays may be a valuable tool for identifying the subset of tumours with functional receptor activation, regardless of mechanism.

show abstract

“…The NSCLC cell lines A549, NCI-H1395, NCI-H1650, NCI-H1666, NCI-H1781, NCI-1975, NCI-H23, NCI-H2126, NCI-H441, NCI-H820, HCC2935, HCC4006, and HCC827 were purchased from ATCC (Manassas, VA, USA). H3255, H3255GR, HCC2279, and PC-9 have been previously described (Ono et al, 2004;Tracy et al, 2004;Engelman et al, 2006). Ma1, and Ma70 are NSCLC cell lines harbouring EGFR mutations that were established at the Kinki University, Osaka, Japan.…”

mentioning

confidence: 99%

Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients

et al. 2008

View full text Add to dashboard Cite

Somatic mutations of LKB1 tumour suppressor gene have been detected in human cancers including non-small cell lung cancer (NSCLC). The relationship between LKB1 mutations and clinicopathological characteristics and other common oncogene mutations in NSCLC is inadequately described. In this study we evaluated tumour specimens from 310 patients with NSCLC including those with adenocarcinoma, adenosquamous carcinoma, and squamous cell carcinoma histologies. Tumours were obtained from patients of US (n ¼ 143) and Korean (n ¼ 167) origin and screened for LKB1, KRAS, BRAF, and EGFR mutations using RT-PCR-based SURVEYOR-WAVE method followed by Sanger sequencing. We detected mutations in the LKB1 gene in 34 tumours (11%). LKB1 mutation frequency was higher in NSCLC tumours of US origin (17%) compared with 5% in NSCLCs of Korean origin (P ¼ 0.001). They tended to occur more commonly in adenocarcinomas (13%) than in squamous cell carcinomas (5%) (P ¼ 0.066). LKB1 mutations associated with smoking history (P ¼ 0.007) and KRAS mutations (P ¼ 0.042) were almost mutually exclusive with EGFR mutations (P ¼ 0.002). The outcome of stages I and II NSCLC patients treated with surgery alone did not significantly differ based on LKB1 mutation status. Our study provides clinical and molecular characteristics of NSCLC, which harbour LKB1 mutations.

show abstract

Gefitinib Induces Apoptosis in the EGFRL858R Non–Small-Cell Lung Cancer Cell Line H3255

Cited by 331 publications

References 19 publications

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

A Multiscale Computational Approach to Dissect Early Events in the Erb Family Receptor Mediated Activation, Differential Signaling, and Relevance to Oncogenic Transformations

Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells

Mutations in the LKB1 tumour suppressor are frequently detected in tumours from Caucasian but not Asian lung cancer patients

Contact Info

Product

Resources

About