Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways

  title={Gefitinib-Sensitizing EGFR Mutations in Lung Cancer Activate Anti-Apoptotic Pathways},
  author={Raffaella Sordella and Daphne W Bell and Daniel A. Haber and Jeffrey Settleman},
  pages={1163 - 1167}
Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRs selectively activate Akt and signal transduction and activator of transcription (STAT) signaling pathways, which promote cell survival, but have no effect on extracellular signal–regulated… 
Gefitinib-Induced Killing of NSCLC Cell Lines Expressing Mutant EGFR Requires BIM and Can Be Enhanced by BH3 Mimetics
It is demonstrated that activation of the proapoptotic BH3-only protein BIM is essential for tumor cell killing and that shutdown of the EGFR–MEK–ERK signaling cascade is critical for BIM activation.
Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival.
The results suggest EGFR status is important in deciding cell fate in response to dasatinib, which could be effective therapy for patients with lung cancers through disruption of cell growth, survival, and tumor invasion.
Induction of BIM Is Essential for Apoptosis Triggered by EGFR Kinase Inhibitors in Mutant EGFR-Dependent Lung Adenocarcinomas
In drug-sensitive EGFR mutant lung cancer cells, induction of BIM is essential for apoptosis triggered by EGFR kinase inhibitors, which implies that the intrinsic pathway of caspase activation may influence sensitivity and/or resistance of EG FR mutant lung tumor cells to EGFR Kinase inhibition.
Nexus of signaling and endocytosis in oncogenesis driven by non-small cell lung cancer-associated epidermal growth factor receptor mutants.
Epidermal growth factor receptor (EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer.
Impaired SHP 2-Mediated Extracellular Signal-Regulated Kinase Activation Contributes to Gefitinib Sensitivity of Lung Cancer Cells with Epidermal Factor Receptor-Citation
It is demonstrated that EGFR-activating mutations may promote some survival pathways but simultaneously impair others, and this multivariate alteration of the network governing cellular response to gefitinib, which is termed “oncogene imbalance”, portends a potentially broader ability to treat gefITinib-resistant NSCLC.
Antitumor Impact of p14ARF on Gefitinib-Resistant Non–Small Cell Lung Cancers
Findings suggest that the region of p14ARF 38-65 a.a. is critical in the pharmacologic action of gefitinib against EGFR-mutated lung adenocarcinoma cells and has potential utility in the therapeutics ofgefit inib-resistant cancers.
Predicting resistance by selection of signaling pathways.
Only by understanding better, and in more depth, complex cancer molecular biology will the authors have the information that will help us to design strategies to augment efficacy of EGFR TKIs and offer patients the best, most correct therapeutic option.
Impaired SHP2-mediated extracellular signal-regulated kinase activation contributes to gefitinib sensitivity of lung cancer cells with epidermal growth factor receptor-activating mutations.
The results show that EGFR-activating mutations may promote some survival pathways but simultaneously impair others, and this multivariate alteration of the network governing cellular response to gefitinib portends a potentially broader ability to treat gefITinib-resistant NSCLC.
Epidermal Growth Factor Receptor Signaling in Nonsmall Cell Lung Cancer
Although women, nonsmokers, patients with adenocarcinoma and patients with Asian ethnicity seem to have better outcomes with erlotinib, the factors predictive for response to these agents are currently the focus of investigation.


ZD1839 (Iressa): an orally active inhibitor of epidermal growth factor signaling with potential for cancer therapy.
In studies with mice bearing a range of human tumor-derived xenografts, ZD1839 given p.o. once a day inhibited tumor growth in a dose-dependent manner and indicated that continuous once-a-day dosing might be a suitable therapeutic regimen.
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib, and these mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor.
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Results suggest that EGFR mutations may predict sensitivity to gefitinib, and treatment with the EGFR kinase inhibitor gefitsinib causes tumor regression in some patients with NSCLC, more frequently in Japan.
Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy
The PI3K/Akt signal transduction cascade has been investigated extensively for its roles in oncogenic transformation. Initial studies implicated both PI3K and Akt in prevention of apoptosis. However,
Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial.
Gefitinib, a well-tolerated oral EGFR-tyrosine kinase inhibitor, improved disease-related symptoms and induced radiographic tumor regressions in patients with NSCLC persisting after chemotherapy.
Roles of ERBB family receptor tyrosine kinases, and downstream signaling pathways, in the control of cell growth and survival.
Potential mechanisms by which modulation of pathway activities following inhibition of ErbB receptor function may alter the sensitivity of cells to toxic insults, leading to increased apoptosis and loss of clonogenic survival are described.
Analysis of signal transducer and activator of transcription 3 (STAT3) in gastrointestinal stromal tumors.
It is demonstrated that STAT3 is constitutively activated in GIST and JAK2 blockade leads to tumor growth inhibition and apoptosis indicating the involvement of the JAK/STAT signaling pathway in Gist cellular survival.
Heterodimerization and functional interaction between EGF receptor family members: a new signaling paradigm with implications for breast cancer research
This review summarizes current work on heterodimerization and attempts to predict the consequences for downstream signaling of the EGF receptor family.
Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention
The current understanding of the Ras/Raf/MEK/ERK signal transduction pathway and the downstream transcription factors is summarized and the prospects of targeting this pathway for therapeutic intervention in leukemia and other cancers will be evaluated.
In BCR-ABL-positive cells, STAT-5 tyrosine-phosphorylation integrates signals induced by imatinib mesylate and Ara-C
It is demonstrated that STAT-5 tyrosine-phosphorylation is a specific target of imatinib mesylate and Ara-C and may be responsible for synergistic or additive effects on BCR-ABL-positive cells.