Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 14 de 14
Filter
Add more filters










Publication year range
1.
Cancer Res ; 84(8): 1303-1319, 2024 04 15.
Article in English | MEDLINE | ID: mdl-38359163

ABSTRACT

The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKI). However, most of these responses are partial, with drug-tolerant residual disease remaining even at the time of maximal response. This residual disease can ultimately lead to relapses, which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived xenograft (PDX) models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the third-generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally distinct from bulk pretreatment tumor. Single-cell transcriptional profiling provided evidence of cells matching the profiles of drug-tolerant cells present in the pretreatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, ASCL1 conferred drug tolerance by initiating an epithelial-to-mesenchymal gene-expression program in permissive cellular contexts. This study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment, and why specific phenotypes are observed only in certain tumors. SIGNIFICANCE: Analysis of residual disease following tyrosine kinase inhibitor treatment identified heterogeneous and context-specific mechanisms of drug tolerance in lung cancer that could lead to the development of strategies to forestall drug resistance. See related commentary by Rumde and Burns, p. 1188.


Subject(s)
Acrylamides , Carcinoma, Non-Small-Cell Lung , Indoles , Lung Neoplasms , Pyrimidines , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , ErbB Receptors/genetics , Drug Resistance, Neoplasm/genetics , Neoplasm Recurrence, Local/drug therapy , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Mutation , Basic Helix-Loop-Helix Transcription Factors/genetics
2.
Cancer Cell ; 41(8): 1516-1534.e9, 2023 08 14.
Article in English | MEDLINE | ID: mdl-37541244

ABSTRACT

Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.


Subject(s)
Lung Neoplasms , Animals , Humans , Chromatin Assembly and Disassembly , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Chromatin , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , ErbB Receptors/genetics , Mutation , Mammals/genetics , DNA Helicases/genetics , Nuclear Proteins/genetics , Transcription Factors/genetics
3.
Nat Commun ; 13(1): 7690, 2022 12 12.
Article in English | MEDLINE | ID: mdl-36509758

ABSTRACT

The brain is a major sanctuary site for metastatic cancer cells that evade systemic therapies. Through pre-clinical pharmacological, biological, and molecular studies, we characterize the functional link between drug resistance and central nervous system (CNS) relapse in Epidermal Growth Factor Receptor- (EGFR-) mutant non-small cell lung cancer, which can progress in the brain when treated with the CNS-penetrant EGFR inhibitor osimertinib. Despite widespread osimertinib distribution in vivo, the brain microvascular tumor microenvironment (TME) is associated with the persistence of malignant cell sub-populations, which are poised to proliferate in the brain as osimertinib-resistant lesions over time. Cellular and molecular features of this poised state are regulated through a Ras homolog family member A (RhoA) and Serum Responsive Factor (SRF) gene expression program. RhoA potentiates the outgrowth of disseminated tumor cells on osimertinib treatment, preferentially in response to extracellular laminin and in the brain. Thus, we identify pre-existing and adaptive features of metastatic and drug-resistant cancer cells, which are enhanced by RhoA/SRF signaling and the brain TME during the evolution of osimertinib-resistant disease.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , rhoA GTP-Binding Protein/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Neoplasm Recurrence, Local/drug therapy , ErbB Receptors/genetics , Aniline Compounds/pharmacology , Aniline Compounds/therapeutic use , Brain/pathology , Mutation , Drug Resistance, Neoplasm/genetics , Tumor Microenvironment
4.
Clin Cancer Res ; 28(17): 3752-3760, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35713632

ABSTRACT

PURPOSE: Dynamic changes in circulating tumor DNA (ctDNA) are under investigation as an early indicator of treatment outcome. EXPERIMENTAL DESIGN: Serial plasma ctDNA (baseline, 8 weeks, and at progression) was prospectively incorporated into the SWOG S1403 clinical trial of afatinib ± cetuximab in tyrosine kinase inhibitor-naïve, EGFR mutation tissue-positive non-small cell lung cancer. RESULTS: EGFR mutations were detected in baseline ctDNA in 77% (82/106) of patients, associated with the presence of brain and/or liver metastases and M1B stage. Complete clearance of EGFR mutations in ctDNA by 8 weeks was associated with a significantly decreased risk of progression, compared with those with persistent ctDNA at Cycle 3 Day 1 [HR, 0.23; 95% confidence interval (CI), 0.12-0.45; P < 0.0001], with a median progression-free survival (PFS) of 15.1 (95% CI, 10.6-17.5) months in the group with clearance of ctDNA versus 4.6 (1.7-7.5) months in the group with persistent ctDNA. Clearance was also associated with a decreased risk of death (HR, 0.44; 95% CI, 0.21-0.90), P = 0.02; median overall survival (OS): 32.6 (23.5-not estimable) versus 15.6 (4.9-28.3) months. CONCLUSIONS: Plasma clearance of mutant EGFR ctDNA at 8 weeks was highly and significantly predictive of PFS and OS, outperforming RECIST response for predicting long-term benefit.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Circulating Tumor DNA , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Circulating Tumor DNA/genetics , Disease-Free Survival , ErbB Receptors/genetics , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Protein Kinase Inhibitors/therapeutic use
5.
J Clin Oncol ; 38(34): 4076-4085, 2020 12 01.
Article in English | MEDLINE | ID: mdl-33021871

ABSTRACT

PURPOSE: The irreversible ErbB family tyrosine kinase inhibitor (TKI) afatinib plus the EGFR monoclonal antibody cetuximab was previously shown to overcome resistance to EGFR TKIs. We studied whether the combination of afatinib plus cetuximab compared with afatinib alone would improve progression-free survival (PFS) in patients with treatment-naive EGFR-mutant non-small-cell lung cancer (NSCLC) by preventing or delaying resistance. METHODS: Patients with EGFR-mutant NSCLC without prior treatment of advanced disease were enrolled in this phase II, multicenter trial and randomly assigned to receive afatinib 40 mg orally daily plus cetuximab 500 mg/m2 intravenously every 2 weeks or afatinib alone. The primary end point was PFS. RESULTS: Between March 25, 2015 and April 23, 2018, 174 patients were randomly assigned, and 168 (83 on afatinib + cetuximab and 85 on afatinib) were eligible. There was no improvement in PFS in patients receiving afatinib plus cetuximab compared with afatinib alone (hazard ratio [HR], 1.01; 95% CI, 0.72 to 1.43; P = .94; median, 11.9 months v 13.4 months). Similarly, there was no difference in response rate (67% v 74%; P = .38) or overall survival (HR, 0.82; 95% CI, 0.50 to 1.36; P = .44). Toxicity was greater with the combination: grade ≥ 3 adverse events related to treatment occurred in 72% of patients receiving afatinib plus cetuximab compared with 40% of those receiving afatinib alone, most commonly rash and diarrhea. Dose reductions were more common in patients receiving the combination, and 30% of patients in this arm discontinued cetuximab due to toxicity. At interim analysis, there was insufficient evidence to support continued accrual, and the trial was closed. CONCLUSIONS: The addition of cetuximab to afatinib did not improve outcomes in previously untreated EGFR-mutant NSCLC, despite recognized activity in the acquired resistance setting.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/drug therapy , Mutation , Adult , Afatinib/administration & dosage , Afatinib/adverse effects , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/enzymology , Carcinoma, Non-Small-Cell Lung/genetics , Cetuximab/administration & dosage , Cetuximab/adverse effects , ErbB Receptors/genetics , Female , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Male , Middle Aged , Progression-Free Survival
6.
Nat Metab ; 1(4): 460-474, 2019 04.
Article in English | MEDLINE | ID: mdl-31535082

ABSTRACT

Drug-tolerance is an acute defense response prior to a fully drug-resistant state and tumor relapse, however there are few therapeutic agents targeting drug-tolerance in the clinic. Here we show that miR-147b initiates a reversible tolerant-state to the EGFR inhibitor osimertinib in non-small cell lung cancer. With miRNA-seq analysis we find that miR-147b is the most upregulated microRNA in osimertinib-tolerant and EGFR mutated lung cancer cells. Whole transcriptome analysis of single-cell derived clones reveals a link between osimertinib-tolerance and pseudohypoxia responses irrespective of oxygen levels. Further metabolomics and genetic studies demonstrate that osimertinib-tolerance is driven by miR-147b repression of VHL and succinate dehydrogenase linked to the tricarboxylic acid cycle and pseudohypoxia pathways. Finally, pretreatment with a miR-147b inhibitor delays osimertinib-associated drug tolerance in patient-derived three-dimensional (3D) structures. This link between miR-147b and tricarboxylic acid cycle may provide promising targets for preventing tumor relapse.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/pharmacology , Cell Hypoxia , Citric Acid Cycle/physiology , Lung Neoplasms/drug therapy , MicroRNAs/physiology , Adenocarcinoma/pathology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Humans , Lung Neoplasms/pathology
7.
Am J Pathol ; 189(6): 1180-1189, 2019 06.
Article in English | MEDLINE | ID: mdl-31079810

ABSTRACT

Easily accessible biomarkers that may inform on the metastatic potential of localized prostate cancer are urgently needed. Herein, we show that syntaphilin (SNPH), a molecule originally identified as a negative regulator of mitochondrial dynamics in neurons, is abundantly expressed in prostate cancer. SNPH distribution in prostate cancer is spatially biphasic, with high expression at the invasive front, correlating with increased proliferative rates, as determined by Ki-67 labeling, and reduced levels in the central tumor bulk, which are further decreased in patients with distant metastases. Higher levels of SNPH are observed with increasing Gleason grade. Prostate tumors predominantly express a novel, extraneuronal isoform of SNPH that accumulates in mitochondria and maintains oxidative metabolism and tumor cell proliferation. These data suggest that SNPH is a novel marker of high Gleason grade prostate cancer, differentially expressed at the invasive front compared with the central tumor bulk, and is potentially down-regulated in metastatic disease. This biphasic pattern of expression may reflect a dual function of SNPH in controlling the balance between cell proliferation and invasion in tumors.


Subject(s)
Biomarkers, Tumor/biosynthesis , Gene Expression Regulation , Membrane Proteins/biosynthesis , Neoplasm Proteins/biosynthesis , Nerve Tissue Proteins/biosynthesis , Prostatic Neoplasms/metabolism , Aged , Aged, 80 and over , Humans , Male , Middle Aged , Neoplasm Grading , Neoplasm Metastasis , Prostatic Neoplasms/pathology , Protein Isoforms/biosynthesis
8.
Cell Rep ; 27(4): 1277-1292.e7, 2019 04 23.
Article in English | MEDLINE | ID: mdl-31018140

ABSTRACT

The brain is a major site of relapse for several cancers, yet deciphering the mechanisms of brain metastasis remains a challenge because of the complexity of the brain tumor microenvironment (TME). To define the molecular landscape of brain metastasis from intact tissue in vivo, we employ an RNA-sequencing-based approach, which leverages the transcriptome of xenografts and distinguishes tumor cell and stromal gene expression with improved sensitivity and accuracy. Our data reveal shifts in epithelial and neuronal-like lineage programs in malignant cells as they adapt to the brain TME and the reciprocal neuroinflammatory response of the stroma. We identify several transcriptional hallmarks of metastasis that are specific to particular regions of the brain, induced across multiple tumor types, and confirmed in syngeneic models and patient biopsies. These data may serve as a resource for exploring mechanisms of TME co-adaptation within, as well as across, different subtypes of brain metastasis.


Subject(s)
Biomarkers, Tumor/genetics , Brain Neoplasms/secondary , Inflammation/pathology , Neoplasms/pathology , Neuronal Plasticity/genetics , Stromal Cells/pathology , Tumor Microenvironment/genetics , Animals , Brain Neoplasms/genetics , Brain Neoplasms/metabolism , Cell Lineage , Female , High-Throughput Nucleotide Sequencing , Humans , Inflammation/genetics , Inflammation/metabolism , Male , Mice , Mice, Nude , Neoplasms/genetics , Neoplasms/metabolism , Stromal Cells/metabolism , Transcriptome , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
9.
Biomed Res Int ; 2017: 7694202, 2017.
Article in English | MEDLINE | ID: mdl-29119113

ABSTRACT

Despite the recent development of immunotherapies that target programmed death-1 (PD-1) or programmed death ligand-1 (PD-L1) in non-small cell lung cancer (NSCLC) treatment, these therapies are less effective in NSCLC patients with epidermal growth factor receptor (EGFR) mutations. However, the molecular mechanisms underlying this lower efficacy of immunotherapies in EGFR mutant lung cancers are still unclear. In this study, we analyzed PD-L1 protein expression in lung cancer cell lines with EGFR mutations prior to and after acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs). We found that parental lung cancer cell lines harboring EGFR mutations showed negative (PC9 and H3255 cells) and positive (HCC827 cells) staining for PD-L1 by immunohistochemistry. Comparing PD-L1 expression between EGFR-TKI resistant cell lines and their parental cells, we found that increased phosphorylation of EGFR was related to increased expression of PD-L1. Increased phosphorylation of EGFR was accompanied by the T790M secondary mutation. Acquired resistance cells with MET amplification or EGFR loss both showed decreased phosphorylation of EGFR and decreased PD-L1 expression. Our results indicate that lung cancer cell lines with EGFR mutations (parental cells) do not harbor high PD-L1 protein expression. In addition, EGFR phosphorylation affects PD-L1 expression after acquisition of resistance to EGFR-TKIs.


Subject(s)
B7-H1 Antigen , Carcinoma, Non-Small-Cell Lung , Drug Resistance, Neoplasm , ErbB Receptors , Gene Expression Regulation, Neoplastic/drug effects , Lung Neoplasms , Mutation, Missense , Neoplasm Proteins , Protein Kinase Inhibitors/pharmacology , Amino Acid Substitution , B7-H1 Antigen/biosynthesis , B7-H1 Antigen/genetics , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/metabolism , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Drug Resistance, Neoplasm/drug effects , Drug Resistance, Neoplasm/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Neoplasm Proteins/genetics , Neoplasm Proteins/metabolism , Phosphorylation/drug effects , Phosphorylation/genetics
10.
Cancer Discov ; 7(12): 1420-1435, 2017 12.
Article in English | MEDLINE | ID: mdl-29025772

ABSTRACT

Mechanisms of acquired resistance to immune checkpoint inhibitors (ICI) are poorly understood. We leveraged a collection of 14 ICI-resistant lung cancer samples to investigate whether alterations in genes encoding HLA Class I antigen processing and presentation machinery (APM) components or interferon signaling play a role in acquired resistance to PD-1 or PD-L1 antagonistic antibodies. Recurrent mutations or copy-number changes were not detected in our cohort. In one case, we found acquired homozygous loss of B2M that caused lack of cell-surface HLA Class I expression in the tumor and a matched patient-derived xenograft (PDX). Downregulation of B2M was also found in two additional PDXs established from ICI-resistant tumors. CRISPR-mediated knockout of B2m in an immunocompetent lung cancer mouse model conferred resistance to PD-1 blockade in vivo, proving its role in resistance to ICIs. These results indicate that HLA Class I APM disruption can mediate escape from ICIs in lung cancer.Significance: As programmed death 1 axis inhibitors are becoming more established in standard treatment algorithms for diverse malignancies, acquired resistance to these therapies is increasingly being encountered. Here, we found that defective antigen processing and presentation can serve as a mechanism of such resistance in lung cancer. Cancer Discov; 7(12); 1420-35. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.


Subject(s)
Drug Resistance, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/drug effects , Histocompatibility Antigens Class I/metabolism , Lung Neoplasms/genetics , Humans , Lung Neoplasms/metabolism , Signal Transduction
11.
Lung Cancer ; 109: 1-8, 2017 07.
Article in English | MEDLINE | ID: mdl-28577937

ABSTRACT

OBJECTIVES: Immunotherapy that targets the programmed death-1/programmed death-ligand 1 (PD-L1) axis has been approved for treatment of non-small cell lung cancer (NSCLC) patients in many countries. However, our current understanding of the role of immunotherapies on NSCLC patients with epidermal growth factor receptor (EGFR) mutation, following acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs), is so far unclear. Especially, there is little data on if each acquired resistance mechanism to EGFR-TKIs alters PD-L1 expression status which is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents. MATERIALS AND METHODS: Lung cancer cell lines (HCC827, HCC4006, PC9, H1975, H358, SW900, and H647) and their daughter cells that acquired resistance to EGFR-TKIs or cytotoxic drugs (cisplatin or vinorelbine) were examined. PD-L1 expression was analyzed by immunohistochemistry, immunoblotting, and/or fluorescent imaging. Published microarray data were also employed to evaluate our findings. RESULTS AND CONCLUSION: We found correlations between therapy-induced E-cadherin downregulation and decreased PD-L1 expression using our cell lines and published microarray data. ShRNA mediated E-cadherin knockdown decreased PD-L1 expression in parental cells, and dual immunofluorescent staining of E-cadherin and PD-L1 suggests co-localization of both molecules. We also observed marked downregulation of PD-L1 in cells with E-cadherin downregulation after chronic treatment with vinorelbine. These results indicate a correlation between therapy-induced E-cadherin downregulation and decreased PD-L1 expression, highlighting the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the evaluation of resistance mechanisms but also for the determination of PD-L1 expression status.


Subject(s)
B7-H1 Antigen/metabolism , Cadherins/metabolism , Carcinoma, Non-Small-Cell Lung/therapy , Immunotherapy/methods , Lung Neoplasms/therapy , Antibodies, Monoclonal , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , B7-H1 Antigen/immunology , Cadherins/genetics , Carcinoma, Non-Small-Cell Lung/immunology , Cell Line, Tumor , Cisplatin/therapeutic use , Down-Regulation , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Erlotinib Hydrochloride/therapeutic use , Gene Expression Regulation, Neoplastic , Humans , Lung Neoplasms/immunology , Protein Transport , RNA, Small Interfering/genetics , Vinblastine/analogs & derivatives , Vinblastine/therapeutic use , Vinorelbine
12.
Cell Rep ; 16(2): 457-471, 2016 07 12.
Article in English | MEDLINE | ID: mdl-27346347

ABSTRACT

Oncogene-induced DNA methylation-mediated transcriptional silencing of tumor suppressors frequently occurs in cancer, but the mechanism and functional role of this silencing in oncogenesis are not fully understood. Here, we show that oncogenic epidermal growth factor receptor (EGFR) induces silencing of multiple unrelated tumor suppressors in lung adenocarcinomas and glioblastomas by inhibiting the DNA demethylase TET oncogene family member 1 (TET1) via the C/EBPα transcription factor. After oncogenic EGFR inhibition, TET1 binds to tumor suppressor promoters and induces their re-expression through active DNA demethylation. Ectopic expression of TET1 potently inhibits lung and glioblastoma tumor growth, and TET1 knockdown confers resistance to EGFR inhibitors in lung cancer cells. Lung cancer samples exhibited reduced TET1 expression or TET1 cytoplasmic localization in the majority of cases. Collectively, these results identify a conserved pathway of oncogenic EGFR-induced DNA methylation-mediated transcriptional silencing of tumor suppressors that may have therapeutic benefits for oncogenic EGFR-mediated lung cancers and glioblastomas.


Subject(s)
ErbB Receptors/genetics , Mixed Function Oxygenases/genetics , Proto-Oncogene Proteins/genetics , Tumor Suppressor Proteins/genetics , Adenocarcinoma/drug therapy , Adenocarcinoma/enzymology , Adenocarcinoma of Lung , Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , Brain Neoplasms/enzymology , CCAAT-Enhancer-Binding Proteins/metabolism , Cell Line, Tumor , CpG Islands , DNA Methylation , Drug Screening Assays, Antitumor , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Gene Expression Regulation, Neoplastic , Gene Silencing , Glioblastoma/drug therapy , Glioblastoma/enzymology , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/enzymology , MAP Kinase Signaling System , Mixed Function Oxygenases/metabolism , Mutation , Oncogenes , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins/metabolism , Transcription, Genetic , Tumor Suppressor Proteins/metabolism , Up-Regulation
13.
Cancer Discov ; 4(5): 606-19, 2014 May.
Article in English | MEDLINE | ID: mdl-24535670

ABSTRACT

Activating mutations in the EGF receptor (EGFR) are associated with clinical responsiveness to EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib. However, resistance eventually arises, often due to a second EGFR mutation, most commonly T790M. Through a genome-wide siRNA screen in a human lung cancer cell line and analyses of murine mutant EGFR-driven lung adenocarcinomas, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene. Erlotinib failed to fully inhibit RAS-ERK signaling when neurofibromin levels were reduced. Treatment of neurofibromin-deficient lung cancers with a MAP-ERK kinase (MEK) inhibitor restored sensitivity to erlotinib. Low levels of NF1 expression were associated with primary and acquired resistance of lung adenocarcinomas to EGFR TKIs in patients. These findings identify a subgroup of patients with EGFR-mutant lung adenocarcinoma who might benefit from combination therapy with EGFR and MEK inhibitors.


Subject(s)
Antineoplastic Agents/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Drug Resistance, Neoplasm , Erlotinib Hydrochloride/administration & dosage , Lung Neoplasms/drug therapy , Neurofibromin 1/genetics , Pyridones/administration & dosage , Pyrimidinones/administration & dosage , Animals , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/genetics , Cell Line, Tumor , Erlotinib Hydrochloride/therapeutic use , Humans , Lung Neoplasms/genetics , MAP Kinase Signaling System , Mice , Neoplasms, Experimental , Neurofibromin 1/metabolism , Pyridones/therapeutic use , Pyrimidinones/therapeutic use
14.
Cancer Discov ; 2(10): 922-33, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22956644

ABSTRACT

EGF receptor (EGFR)-mutant lung cancers eventually become resistant to treatment with EGFR tyrosine kinase inhibitors (TKI). The combination of EGFR-TKI afatinib and anti-EGFR antibody cetuximab can overcome acquired resistance in mouse models and human patients. Because afatinib is also a potent HER2 inhibitor, we investigated the role of HER2 in EGFR-mutant tumor cells. We show in vitro and in vivo that afatinib plus cetuximab significantly inhibits HER2 phosphorylation. HER2 overexpression or knockdown confers resistance or sensitivity, respectively, in all studied cell line models. FISH analysis revealed that HER2 was amplified in 12% of tumors with acquired resistance versus only 1% of untreated lung adenocarcinomas. Notably, HER2 amplification and EGFR(T790M) were mutually exclusive. Collectively, these results reveal a previously unrecognized mechanism of resistance to EGFR-TKIs and provide a rationale to assess the status and possibly target HER2 in EGFR-mutant tumors with acquired resistance to EGFR-TKIs.


Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Receptor, ErbB-2/metabolism , Adenocarcinoma/metabolism , Adenocarcinoma of Lung , Afatinib , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Cell Line, Tumor , Cetuximab , Class I Phosphatidylinositol 3-Kinases , ErbB Receptors/metabolism , Erlotinib Hydrochloride , Humans , Lung Neoplasms/metabolism , Mice , Mice, Nude , Molecular Targeted Therapy , Mutation , Phosphatidylinositol 3-Kinases/genetics , Phosphorylation/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Quinazolines/pharmacology , Quinazolines/therapeutic use , RNA Interference , RNA, Small Interfering , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...