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

Lung cancer is the most common tumor-related cause of death in western industrialized countries, despite continuous improvement in both diagnostic and therapeutic approaches. Since epidermal growth factor receptor (EGFR) is overexpressed in 80% of cases of non-small cell lung carcinoma, mediating important carcinogenic properties such as cell-cycle progression, apoptosis, angiogenesis and metastasis, it is considered a relevant target in novel specific therapies. This has lead to the development of the low-molecular EGFR tyrosine kinase inhibitors (EGFR-TKI) Gefitinib and Erlotinib. Predicting which patients will respond to an EGFR-targeted therapy is of particular clinical interest. Recent studies show a significantly better response and prolonged progression-free survival in patients with EGFR-mutated tumors, even when used as first-line therapy. Moreover, genetic mutations which correlate to primary EGFR-TKI resistance (e.g. KRAS) or produce secondary resistance to known TKI (e.g. EGFR mutation T790 M or MET amplification) have meanwhile been explained. Predictive diagnosis of these mutations using histological material is becoming increasingly important for patient stratification and will soon be indispensable not only for lung cancer.
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PMID:[Molecular diagnostics in lung carcinoma for therapy stratification]. 1999 36

Seventy-five percent of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations respond to treatment with the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib; however, drug-resistant tumors eventually emerge. In 60% of cases, resistant tumors carry a secondary mutation in EGFR (T790M), amplification of MET, or both. Here, we describe the establishment of erlotinib resistance in lung tumors, which were induced by mutant EGFR, in transgenic mice after multiple cycles of drug treatment; we detect the T790M mutation in five out of 24 tumors or Met amplification in one out of 11 tumors in these mice. This preclinical mouse model, therefore, recapitulates the molecular changes responsible for resistance to TKIs in human tumors and holds promise for the discovery of additional mechanisms of drug resistance in lung cancer.
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PMID:Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma. 2000 86

MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.
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PMID:Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. 2012 49

The MET tyrosine kinase signaling pathway is upregulated in many cancers, including lung cancer. The pathway normally promotes mitosis, cell motility and cell survival; but in cancer it can also promote cell proliferation, invasion, metastasis and angiogenesis. The activating ligand, hepatocyte growth factor (HGF) is normally secreted by fibroblasts and smooth muscle cells, but can also be produced by tumor cells. MET upregulation in lung cancer is caused by overexpression and mutation. These mutations can vary with ethnicity. MET signaling affects cytoskeletal proteins such as paxillin, which participates in cell adhesion, growth and motility. Therapeutic approaches that block MET signaling are being studied, and include the use of: small interference RNA, Geldanamycin, competitive HGF homologues, decoy receptors and direct MET inhibitors such as K252a, SU11274, PHA665752 and PF2341066. It is hoped that blocking MET signaling may one day become an effective treatment for some lung cancers.
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PMID:MET molecular mechanisms and therapies in lung cancer. 2013 96

MET, the receptor for HGF, has recently been identified as a novel promising target in several human malignancies, including non-small-cell lung cancer (NSCLC). Deregulation of the HGF/MET signaling pathway can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. While the role of MET mutations in NSCLC is not yet fully understood, MET amplification emerged as a critical event in driving cell survival, with preclinical data suggesting that MET-amplified cell lines are exquisitely sensitive to MET inhibition. True MET amplification, which has been associated with poor prognosis in different retrospective series, is a relatively uncommon event in NSCLC, occurring in 1-7% of unselected cases. Nevertheless, in highly selected cohorts of patients, such as those harboring somatic mutations of the EGF receptor (EGFR) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), MET amplification can be observed in up to 20% of cases. Preclinical data suggested that a treatment approach including a combination of EGFR and MET TKIs could be an effective strategy in this setting and led to the clinical investigation of multiple MET TKIs in combination with erlotinib. Results from ongoing and future trials will clarify the role of MET TKIs for the treatment of NSCLC and will provide insights into the most appropriate timing for their use.
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PMID:Clinical implications of MET gene copy number in lung cancer. 2014 83

ErbB3 is a critical activator of phosphoinositide 3-kinase (PI3K) signaling in epidermal growth factor receptor (EGFR; ErbB1), ErbB2 [human epidermal growth factor receptor 2 (HER2)], and [hepatocyte growth factor receptor (MET)] addicted cancers, and reactivation of ErbB3 is a prominent method for cancers to become resistant to ErbB inhibitors. In this study, we evaluated the in vivo efficacy of a therapeutic anti-ErbB3 antibody, MM-121. We found that MM-121 effectively blocked ligand-dependent activation of ErbB3 induced by either EGFR, HER2, or MET. Assessment of several cancer cell lines revealed that MM-121 reduced basal ErbB3 phosphorylation most effectively in cancers possessing ligand-dependent activation of ErbB3. In those cancers, MM-121 treatment led to decreased ErbB3 phosphorylation and, in some instances, decreased ErbB3 expression. The efficacy of single-agent MM-121 was also examined in xenograft models. A machine learning algorithm found that MM-121 was most effective against xenografts with evidence of ligand-dependent activation of ErbB3. We subsequently investigated whether MM-121 treatment could abrogate resistance to anti-EGFR therapies by preventing reactivation of ErbB3. We observed that an EGFR mutant lung cancer cell line (HCC827), made resistant to gefitinib by exogenous heregulin, was resensitized by MM-121. In addition, we found that a de novo lung cancer mouse model induced by EGFR T790M-L858R rapidly became resistant to cetuximab. Resistance was associated with an increase in heregulin expression and ErbB3 activation. However, concomitant cetuximab treatment with MM-121 blocked reactivation of ErbB3 and resulted in a sustained and durable response. Thus, these results suggest that targeting ErbB3 with MM-121 can be an effective therapeutic strategy for cancers with ligand-dependent activation of ErbB3.
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PMID:An ErbB3 antibody, MM-121, is active in cancers with ligand-dependent activation. 2021 4

Renal clear cell carcinomas represent about 3% of all visceral cancers and account for approximately 85% of renal cancers in adults. Environmental and genetic factors are involved in the development of renal cancer. Although to date there are 19 hereditary syndromes described in which renal cell cancer may occur, only four syndromes with an unequivocal genetic predisposition to renal cell carcinoma have been identified: VHL syndrome (mutations in the VHL gene), hereditary clear cell carcinoma (translocations t(3:8), t(2:3)), hereditary papillary carcinoma (mutations in the MET protooncogene) and tuberous sclerosis (mutations in the TSC1 and TSC2 genes). Little is known genetically about the other forms of familial renal cell cancer. Since there is a growing awareness about the necessity of early intervention, clinical criteria have been developed that aid in the identification of hereditary forms of renal cancer. The aim of the current study was to identify minimal inclusion criteria so that nuclear pedigree families can be ascertained for risk assessment and/or kidney tumour screening. The results reveal that inclusion features described herein, such as (a) renal clear cell cancer diagnosed before 55 years of age, and (b) renal clear cell cancer and gastric cancer or lung cancer among first degree relatives, are useful in identifying suspected hereditary clear cell renal cancer patients.
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PMID:Nuclear Pedigree Criteria for the Identification of Individuals Suspected to be at Risk of an Inherited Predisposition to Renal Cancer. 2022 38

We document an EGFR mutation in a patient with papillary renal cell cancer with a history of multiple therapies, including interferon-alpha, interleukin-2, 5-fluorouracil, and interferon-alpha together with 13-cis-retinoic acid, to which floxuridine was later added, and thalidomide maintenance therapy for six years. We provide a succinct review of the PubMed-derived literature on EGFR mutations in diverse tumors, which indicates that a subset of patients with various tumor types may harbor EGFR mutations. A 32-year old woman with sporadic, metastatic papillary renal cancer was found to harbor an EGFR kinase domain mutation in addition to the MET kinase mutation typically found in this disease. Since lung cancer patients with EGFR mutations often respond well to EGFR inhibitor therapy and EGFR mutations occur in a variety of tumors, it should be worthwhile to assess EGFR status prospectively in other tumors and study the results of treatment with EGFR inhibitors in these patients.
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PMID:Epidermal growth factor receptor mutation and diverse tumors: case report and concise literature review. 2034 42

The epidermal growth factor receptor (EGFR) and its ligands are frequently expressed in non-small-cell lung cancer (NSCLC). The EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib have shown clinical activity in NSCLC. However, only a small subgroup of NSCLC patients respond to these agents, suggesting that patients' selection is critical for TKIs sensitivity. In this regard, several studies have tried to individuate prognostic and predictive factors that are associated with sensitivity or resistance to anti-EGFR agents. A strong correlation between activating mutations in the EGFR-TK domain and response to erlotinib and gefitinib has been reported in different trials. However, patients without EGFR mutations might also benefit of treatment with these drugs by experiencing prolonged disease stabilization. No significant correlation between EGFR overexpression and response to treatment has been found, while controversial results have been reported regarding the association between EGFR gene amplification and clinical response to TKIs. Different mechanisms of resistance to EGFR-TKIs have also been described. Mutations of KRAS, that occur in approximately 20% of NSCLC, are associated with reduced response to EGFR-TKIs. The EGFR T790M mutation, that reduces the affinity of the EGFR to gefitinib and erlotinib, and MET gene amplification produce acquired resistance to anti-EGFR agents. Taken together, these findings suggest that several different molecular alterations regulate the sensitivity of NSCLC cells to EGFR-TKIs, and that a comprehensive approach to this phenomenon is necessary for an appropriate selection of patients that should be treated with these drugs.
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PMID:Predictive biomarkers to tyrosine kinase inhibitors for the epidermal growth factor receptor in non-small-cell lung cancer. 2038 64

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, are the first targeted therapy drugs approved for the treatment of advanced non-small-cell lung cancer (NSCLC). Interestingly, treatment with these small molecule, reversible EGFR-TKIs leads to more positive response rates in patients with adenocarcinoma, in females, Asians, and patients with no history of smoking. Positive responses to treatment in these populations may be due to the increased prevalence of mutations in the EGFR gene. Several distinct mutations in the EGFR gene have been identified in specimens from patients with NSCLC who responded to treatment with anilinoquinazoline EGFR inhibitors. However, despite the dramatic initial response to TKIs, most lung cancer patients relapse and subsequently become resistant to the drug, a process termed acquired resistance. The precise mechanisms underlying acquired resistance remain unclear. Resistance to EGFR-TKIs could result from several potential mechanisms, including development of a secondary mutation in EGFR (such as T790M), amplification of the MET receptor tyrosine kinase gene, or overexpression of other receptor tyrosine kinases.
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PMID:Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib. 2040 20


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