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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases (RTK). EGFR overexpression or mutation in many different forms of cancers has highlighted its role as an important therapeutic target. Gefitinib, the first small molecule inhibitor of EGFR kinase function to be approved for the treatment of nonsmall cell lung cancer (NSCLC) by the FDA, demonstrates clinical activity primarily in patients with tumors that harbor somatic kinase domain mutations in EGFR. Here, we compare wild-type EGFR autophosphorylation kinetics to the L834R (also called L858R) EGFR form, one of the most common mutations in lung cancer patients. Using rapid chemical quench, time-resolved electrospray mass spectrometry (ESI-MS), and Western blot analyses, we examined the order of autophosphorylation in wild-type (WT) and L834R EGFR and the effect of gefitinib (Iressa) on the phosphorylation of individual tyrosines. These studies establish that there is a temporal order of autophosphorylation of key tyrosines involved in downstream signaling for WT EGFR and a loss of order for the oncogenic L834R mutant. These studies also reveal unique signature patterns of drug sensitivity for inhibition of tyrosine autophosphorylation by gefitinib: distinct for WT and oncogenic L834R mutant forms of EGFR. Fluorescence studies show that for WT EGFR the binding affinity for gefitinib is weaker for the phosphorylated protein while for the oncogenic mutant, L834R EGFR, the binding affinity of gefitinib is substantially enhanced and likely contributes to the efficacy observed clinically. This mechanistic information is important in understanding the molecular details underpinning clinical observations as well as to aid in the design of more potent and selective EGFR inhibitors.
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PMID:Temporal resolution of autophosphorylation for normal and oncogenic forms of EGFR and differential effects of gefitinib. 2265 99

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, such as gefitinib and erlotinib, are effective for non-small cell lung cancer with activating EGFR mutations. However, even in patients with an initial dramatic response to such a drug, acquired resistance develops after 6-12 months. A secondary mutation of T790M in EGFR and amplification of the MET gene account for this resistance; however, the mechanism(s) of approximately 30% of acquired resistance cases remain unknown. We established an erlotinib-resistant lung cancer cell line named PC-9/ER3 that harbors an EGFR mutation after continuously exposing PC-9 cells to erlotinib. PC-9/ER3 cells were 136-fold more resistant to erlotinib than the parental cells. Although the PC-9/ER3 cells did not carry the T790M mutation or MET amplification and had similar levels of phosphorylated (p) STAT3, pJAK2 increased in the resistant cells. It was found in the present study that 3-12 h of exposure to erlotinib in both cell lines did not affect pJAK2 expression, but did result in increased pSTAT3 expression. pAkt in PC-9/ER3 cells was less suppressed than in PC-9 cells, although pEGFR and pMAPK were markedly suppressed in both cell lines. The combined treatment of erlotinib plus a JAK2 inhibitor (JSI-124) suppressed pAkt in PC-9/ER3 cells. Similarly, the combination of erlotinib plus JSI-124 or siRNA against JAK2 restored sensitivity to erlotinib in PC-9/ER3 cells. The combination of erlotinib plus JSI-124 was also effective for reducing PC-9/ER3 tumors in a murine xenograft model. Our results suggest that the activation of JAK2 partially accounts for acquired erlotinib resistance.
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PMID:JAK2-related pathway induces acquired erlotinib resistance in lung cancer cells harboring an epidermal growth factor receptor-activating mutation. 2271 64

Epidermal growth factor receptor (EGFR) mutations play a predictive role in advanced stages of non-small-cell lung cancer (NSCLC) patients. We conducted this study in order to assess EGFR status in a Portuguese population and its role in NSCLC patients' outcomes. Patients were submitted to EGFR assessment by high-resolution melting and/or direct sequencing. Kaplan-Meier curve was used to assess overall survival and progression-free survival (PFS). Two hundred forty eight out of 322 participants were assessed for EGFR status. Forty-two patients (16.9 %) presented EGFR-mutated status: one patient (2.4 %) presented exon 18; 21 patients (50 %), exon 19; one patient (2.4 %), exon 20; and 18 patients (45.2 %), exon 21 mutations, p < 0.001. PFS was not assessed (n.a.) for patient with exon 18 mutation, and for the other patients with mutations, it was 7 months (3.96-10.03) (exon 19), <1 month (exon 20), and 7 months (0-14.2) (exon 21) (p = 0.027). Overall survival (OS) was 11 months (exon 18), 11 months (1-18) (exon 19), 1 month (exon 20), and 7.5 months (2-70) (exon 21) (p = n.a). This study suggests that the EGFR mutation is herein observed in a higher proportion than expected for a Caucasian population, and OS is a little less than that published in the literature.
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PMID:EGFR exon mutation distribution and outcome in non-small-cell lung cancer: a Portuguese retrospective study. 2284 17

Epidermal growth factor receptor inhibitors are used to treat advanced lung cancer patients for almost a decade. Current knowledge on their role in the first or subsequent lines of therapy serves as a model for other targeted therapies in development. Several molecular predictors of outcomes were successfully identified in preclinical and clinical studies. Evaluation of EGFR-activating mutations is currently used to define biologically distinct patient subsets with important consequences for prognosis and therapy. Ongoing translational and clinical research exploring EGFR inhibition in lung cancer focuses on better understanding of biology of EGFR-driven disease, efficacy of novel irreversible EGFR inhibitors and monoclonal antibodies, efficacy of combination strategies, and attempts to move EGFR inhibitors into therapy portfolio for early-stage disease.
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PMID:Epidermal growth factor receptor (EGFR) inhibitors and derived treatments. 2298 61

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) were initially established as second- or third-line treatment of advanced non-small-cell lung cancer (NSCLC). Subsequent studies, including IPASS, OPTIMAL, and EURTAC, have demonstrated that these TKIs are effective first-line therapeutic options in patients with tumors harboring activating mutations in the EGFR gene. The TKIs are better tolerated than conventional chemotherapy, with frequent yet mild side effects such as rash and diarrhea, and rarely interstitial lung disease. Because most patients on TKIs develop resistance due to a variety of mechanisms, the use of TKIs in the acquired-resistance setting and in the setting of earlier-staged cancers is being extensively studied. Here we review the major trials leading to the established use of EGFR TKIs in NSCLC, followed by discussion of recently completed and ongoing trials using the next-generation EGFR inhibitor afatinib.
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PMID:First-line treatment of EGFR-mutant non-small-cell lung cancer: the role of erlotinib and other tyrosine kinase inhibitors. 2305 91

Epidermal growth factor receptor (EGFR) gene mutations and increased EGFR copy numbers have been associated with a favorable response to EGFR tyrosine kinase inhibitors (TKI) in patients with non-small-cell lung cancer (NSCLC), and several markers have been identified that predict response to treatment. Lung adenocarcinomas also harbor activating mutations in the downstream GTPase, v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and mutations in EGFR and KRAS appear to be mutually exclusive. Even though KRAS mutations were identified in NSCLC tumors more than 20 years ago, we have only just begun to appreciate the clinical value of determining KRAS tumor status. Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy and do not respond to EGFR inhibitors. There is a clear need for therapies specifically developed for patients with KRAS-mutant NSCLC. In this review, we summarize the clinical and pathologic characteristics of patients with NSCLC and with KRAS mutations, describe work that explores the predictive and prognostic influence of KRAS mutations, and provide an overview of the "synthetic lethal" interactions and current approaches to targeting KRAS-mutant NSCLC.
Clin Lung Cancer 2013 May
PMID:KRAS mutations in lung cancer. 2312 93

Epidermal growth factor receptor (EGFR) pathway activation is a frequent event in human carcinomas. Mutations in EGFR itself are, however, rare, and the mechanisms regulating EGFR activation remain elusive. Leucine-rich immunoglobulin repeats-1 (LRIG1), an inhibitor of EGFR activity, is one of four genes identified that predict patient survival across solid tumour types including breast, lung, melanoma, glioma, and bladder. We show that deletion of Lrig1 is sufficient to promote murine airway hyperplasia through loss of contact inhibition and that re-expression of LRIG1 in human lung cancer cells inhibits tumourigenesis. LRIG1 regulation of contact inhibition occurs via ternary complex formation with EGFR and E-cadherin with downstream modulation of EGFR activity. We find that LRIG1 LOH is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. Our findings imply that the early stages of squamous carcinoma development are driven by a change in amplitude of EGFR signalling governed by the loss of contact inhibition.
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PMID:LRIG1 regulates cadherin-dependent contact inhibition directing epithelial homeostasis and pre-invasive squamous cell carcinoma development. 2320 28

Epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC) is a strong predictive factor for a favorable response to EGFR tyrosine kinase inhibitors, however, its prognostic role in locally advanced stage is unclear. The aim of this study was to analyze the association of EGFR mutational status and clinical outcome after neoadjuvant chemoradiotherapy (CRT) followed by surgical resection in mediastinoscopically proven N2(+) NSCLC patients. We retrospectively identified 168 patients diagnosed between 1998 and 2006. EGFR mutational status was identified in 107 patients. Response and survival after neoadjuvant CRT followed by surgery were compared according to EGFR mutational status. 83 patients (77.6%) were found to have wild type EGFR, while exon 19 deletions or L858R missense mutations in the EGFR gene were detected in 19 patients. There was no significant difference in overall survival; however, the 5-year PFS rate in EGFR mutant patients (8.4%) were significantly lower than in the EGFR wild-type patients (33.6%; p=0.005). In multivariate analysis, EGFR mutation was a significant prognostic factor for a higher risk of distant recurrence/progression than the EGFR wild type (HR=7.183, p=0.005). In locally advanced mediastinoscopic N2-positive NSCLC, EGFR mutation was associated with more frequent distant relapses and worse 5-year PFS rate after neoadjuvant CRT followed by surgery, which might suggest that systemic control might be important in patients with the EGFR mutation. Therefore, the role of TKI for adjuvant EGFR TKI to decrease disease recurrence in distant sites should be further investigated.
Lung Cancer 2013 Mar
PMID:Epidermal growth factor receptor mutation and treatment outcome of mediastinoscopic N2 positive non-small cell lung cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery. 2326 Nov 44

Lung cancer is the most common cause of cancer deaths. Most patients present with advanced-stage disease, and the prognosis is generally poor. However, with the understanding of lung cancer biology, and development of molecular targeted agents, there have been improvements in treatment outcomes for selected subsets of patients with non-small-cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated significantly improved tumor responses and progression-free survival in subsets of patients with advanced NSCLC, particularly those with tumors harboring activating EGFR mutations. Testing for EGFR mutations is a standard procedure for identification of patients who will benefit from first-line EGFR TKIs. For patients with advanced NSCLC and no activating EGFR mutations (EGFR wild-type) or no other driving oncogenes such as ALK-gene rearrangement, chemotherapy is still the standard of care. A new generation of EGFR TKIs, targeting multiple receptors and with irreversible bindings to the receptors, are in clinical trials and have shown encouraging effects. Research on primary and acquired resistant mechanisms to EGFR TKIs are ongoing. Monoclonal antibodies (e.g. cetuximab), in combination with chemotherapy, have demonstrated improved outcomes, particularly for subsets of NSCLC patients, but further validations are needed. Novel monoclonal antibodies are combined with chemotherapy, and randomized comparative studies are ongoing. This review summarizes the current status of EGFR inhibitors in NSCLC in 2012 and some of the major challenges we are facing.
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PMID:Epidermal growth factor receptor inhibition in lung cancer: status 2012. 2337 Mar 15

Although cancers may have many genetic alterations, there are only a few mutations actually associated with essential traits of cancer cells such as cell proliferation or evasion from apoptosis. Because cancer cells are "addicted" to these "drive genes" , pharmacologic inhibition of these gene function is highly effective. Epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitor(TKI)(such as gefitinib or erlotinib)treatment of lung cancer harboring EGFR gene mutation is one of the prototypes of such therapies. Several clinical trials clearly demonstrated that progression-free survival of patients treated with EGFR-TKI is significantly longer than that of those treated by conventional platinum doublet chemotherapy. EGFR-TKI therapy dramatically changed the paradigm of lung cancer treatment. Furthermore, in 2012, crizotinib was approved for lung cancer treatment with anaplastic lymphoma kinase(ALK)gene translocation. Targeted therapies for lung cancers "addicted" to other driver gene mutations including ROS1, RET or HER2 are also under development. Through these personalized approaches, lung cancer is changing from an acute fatal disease to a more chronic disease, and eventually we might be able to cure it.
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PMID:[Driver gene mutation and targeted therapy of lung cancer]. 2350 88


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