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lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling.
Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, Singh B, Franklin JL, Wang J, Hu H, Wei T, Yang M, Yeatman TJ, Lee E, Saito-Diaz K, Hinger S, Patton JG, Chung CH, Emmrich S, Klusmann JH, Fan D, Coffey RJ
(2017) Nat Med 23: 1331-1341
MeSH Terms: Antineoplastic Agents, Immunological, Cell Line, Tumor, Cetuximab, Disease Progression, Drug Resistance, Neoplasm, Epigenesis, Genetic, GATA6 Transcription Factor, Humans, MicroRNAs, RNA, Long Noncoding, Signal Transduction, Wnt Proteins, beta Catenin
Show Abstract · Added April 3, 2018
De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.
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MeSH Terms
Three-dimensional culture system identifies a new mode of cetuximab resistance and disease-relevant genes in colorectal cancer.
Li C, Singh B, Graves-Deal R, Ma H, Starchenko A, Fry WH, Lu Y, Wang Y, Bogatcheva G, Khan MP, Milne GL, Zhao S, Ayers GD, Li N, Hu H, Washington MK, Yeatman TJ, McDonald OG, Liu Q, Coffey RJ
(2017) Proc Natl Acad Sci U S A 114: E2852-E2861
MeSH Terms: Animals, Antineoplastic Agents, Immunological, Cell Culture Techniques, Cell Line, Tumor, Cetuximab, Colorectal Neoplasms, Crizotinib, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Humans, Hydroxyprostaglandin Dehydrogenases, Mice, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Pyrazoles, Pyridines, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Tissue Array Analysis, Versicans, Xenograft Model Antitumor Assays
Show Abstract · Added May 3, 2017
We previously reported that single cells from a human colorectal cancer (CRC) cell line (HCA-7) formed either hollow single-layered polarized cysts or solid spiky masses when plated in 3D in type-I collagen. To begin in-depth analyses into whether clonal cysts and spiky masses possessed divergent properties, individual colonies of each morphology were isolated and expanded. The lines thus derived faithfully retained their parental cystic and spiky morphologies and were termed CC (cystic) and SC (spiky), respectively. Although both CC and SC expressed EGF receptor (EGFR), the EGFR-neutralizing monoclonal antibody, cetuximab, strongly inhibited growth of CC, whereas SC was resistant to growth inhibition, and this was coupled to increased tyrosine phosphorylation of MET and RON. Addition of the dual MET/RON tyrosine kinase inhibitor, crizotinib, restored cetuximab sensitivity in SC. To further characterize these two lines, we performed comprehensive genomic and transcriptomic analysis of CC and SC in 3D. One of the most up-regulated genes in CC was the tumor suppressor , and the most up-regulated gene in SC was () in 3D and xenografts. Analysis of a CRC tissue microarray showed that epithelial, but not stromal, VCAN staining strongly correlated with reduced survival, and combined epithelial VCAN and absent HPGD staining portended a poorer prognosis. Thus, with this 3D system, we have identified a mode of cetuximab resistance and a potential prognostic marker in CRC. As such, this represents a potentially powerful system to identify additional therapeutic strategies and disease-relevant genes in CRC and possibly other solid tumors.
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22 MeSH Terms
In Vivo Autofluorescence Imaging of Tumor Heterogeneity in Response to Treatment.
Shah AT, Diggins KE, Walsh AJ, Irish JM, Skala MC
(2015) Neoplasia 17: 862-870
MeSH Terms: Antineoplastic Agents, Cell Line, Tumor, Cell Proliferation, Cetuximab, Cisplatin, Flavin-Adenine Dinucleotide, Humans, Microscopy, Fluorescence, Multiphoton, NADP, Neoplasms, Oxidation-Reduction, Single-Cell Analysis, Time Factors, Tumor Burden, Xenograft Model Antitumor Assays
Show Abstract · Added December 24, 2015
Subpopulations of cells that escape anti-cancer treatment can cause relapse in cancer patients. Therefore, measurements of cellular-level tumor heterogeneity could enable improved anti-cancer treatment regimens. Cancer exhibits altered cellular metabolism, which affects the autofluorescence of metabolic cofactors NAD(P)H and FAD. The optical redox ratio (fluorescence intensity of NAD(P)H divided by FAD) reflects global cellular metabolism. The fluorescence lifetime (amount of time a fluorophore is in the excited state) is sensitive to microenvironment, particularly protein-binding. High-resolution imaging of the optical redox ratio and fluorescence lifetimes of NAD(P)H and FAD (optical metabolic imaging) enables single-cell analyses. In this study, mice with FaDu tumors were treated with the antibody therapy cetuximab or the chemotherapy cisplatin and imaged in vivo two days after treatment. Results indicate that fluorescence lifetimes of NAD(P)H and FAD are sensitive to early response (two days post-treatment, P<.05), compared with decreases in tumor size (nine days post-treatment, P<.05). Frequency histogram analysis of individual optical metabolic imaging parameters identifies subpopulations of cells, and a new heterogeneity index enables quantitative comparisons of cellular heterogeneity across treatment groups for individual variables. Additionally, a dimensionality reduction technique (viSNE) enables holistic visualization of multivariate optical measures of cellular heterogeneity. These analyses indicate increased heterogeneity in the cetuximab and cisplatin treatment groups compared with the control group. Overall, the combination of optical metabolic imaging and cellular-level analyses provide novel, quantitative insights into tumor heterogeneity.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
2 Communities
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15 MeSH Terms
[(18)F]-FLT PET to predict early response to neoadjuvant therapy in KRAS wild-type rectal cancer: a pilot study.
McKinley ET, Watchmaker JM, Chakravarthy AB, Meyerhardt JA, Engelman JA, Walker RC, Washington MK, Coffey RJ, Manning HC
(2015) Ann Nucl Med 29: 535-42
MeSH Terms: Adult, Antineoplastic Agents, Cetuximab, Chemoradiotherapy, Dideoxynucleosides, Female, Follow-Up Studies, Humans, Immunohistochemistry, Male, Middle Aged, Multimodal Imaging, Neoadjuvant Therapy, Pilot Projects, Positron-Emission Tomography, Proto-Oncogene Proteins p21(ras), Radiopharmaceuticals, Rectal Neoplasms, Tomography, X-Ray Computed, Treatment Outcome
Show Abstract · Added July 28, 2015
OBJECT - This pilot study evaluated the utility of 3'-deoxy-3'[18F]-fluorothymidine ([(18)F]-FLT) positron emission tomography (PET) to predict response to neoadjuvant therapy that included cetuximab in patients with wild-type KRAS rectal cancers.
METHODS - Baseline [(18)F]-FLT PET was collected prior to treatment initiation. Follow-up [(18)F]-FLT was collected after three weekly infusions of cetuximab, and following a combined regimen of cetuximab, 5-FU, and radiation. Imaging-matched biopsies were collected with each PET study.
RESULTS - Diminished [(18)F]-FLT PET was observed in 3/4 of patients following cetuximab treatment alone and in all patients following combination therapy. Reduced [(18)F]-FLT PET following combination therapy predicted disease-free status at surgery. Overall, [(18)F]-FLT PET agreed with Ki67 immunoreactivity from biopsy samples and surgically resected tissue, and was predictive of treatment-induced rise in p27 levels.
CONCLUSION - These results suggest that [(18)F]-FLT PET is a promising imaging biomarker to predict response to neoadjuvant therapy that included EGFR blockade with cetuximab in patients with rectal cancer.
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20 MeSH Terms
A randomized phase II efficacy and correlative studies of cetuximab with or without sorafenib in recurrent and/or metastatic head and neck squamous cell carcinoma.
Gilbert J, Schell MJ, Zhao X, Murphy B, Tanvetyanon T, Leon ME, Neil Hayes D, Haigentz M, Saba N, Nieva J, Bishop J, Sidransky D, Ravi R, Bedi A, Chung CH
(2015) Oral Oncol 51: 376-82
MeSH Terms: Adult, Aged, Antineoplastic Agents, Carcinoma, Squamous Cell, Cetuximab, Female, Head and Neck Neoplasms, Humans, Male, Middle Aged, Neoplasm Metastasis, Niacinamide, Phenylurea Compounds, Recurrence, Sorafenib
Show Abstract · Added February 17, 2015
INTRODUCTION - A combination of cetuximab and sorafenib in patients with recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) were assessed for potential benefit.
MATERIAL AND METHODS - In a randomized phase II study, R/M HNSCC patients were treated with cetuximab 400mg/m(2) IV on day 1 followed by 250mg/m(2) IV weekly (Arm A), or cetuximab at the same dose/schedule plus sorafenib 400mg PO twice-a-day (Arm B). Each cycle was 21days. Tumor p16 and HPV status, and plasma immunomodulatory cytokine levels were assessed.
RESULTS - Of 55 patients enrolled (Arm A-27, Arm B-28), 52 patients received assigned treatments and 43 were evaluable for response. Overall response rate was 8% for both arms. Median overall survival (OS) and progression-free survival (PFS) were 9.0 and 3.0months in Arm A, and 5.7 and 3.2months in Arm B, respectively. Forty-four patients had tumors available for p16 staining (35-negative, 9-positive). Three of nine p16-positive tumors were also HPV positive. The p16-negative patients had significantly better PFS compared to the p16-positive patients (3.7 vs. 1.6months; p-value: 0.03), regardless of study arms. Twenty-four plasma samples were tested for 12 cytokine levels and patients with higher TGFβ1 levels had inferior PFS compared to lower levels (1.9 vs. 4.7months; adjusted p-value: 0.015), regardless of study arms.
CONCLUSIONS - A subset of R/M patients with p16-negative tumors or lower plasma TGFβ1 levels had longer PFS given the cetuximab-based therapy. However, both arms showed only modest response and sorafenib given with cetuximab did not demonstrate clinical benefit.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Annotation of human cancers with EGFR signaling-associated protein complexes using proximity ligation assays.
Smith MA, Hall R, Fisher K, Haake SM, Khalil F, Schabath MB, Vuaroqueaux V, Fiebig HH, Altiok S, Chen YA, Haura EB
(2015) Sci Signal 8: ra4
MeSH Terms: Animals, Antibodies, Monoclonal, Humanized, Biomarkers, Tumor, Cell Line, Tumor, Cetuximab, ErbB Receptors, GRB2 Adaptor Protein, Heterografts, Humans, Immunoassay, Lung Neoplasms, Mice, Multiprotein Complexes, Protein Interaction Mapping, Signal Transduction
Show Abstract · Added April 18, 2017
Strategies to measure functional signaling-associated protein complexes have the potential to augment current molecular biomarker assays, such as genotyping and expression profiling, used to annotate diseases. Aberrant activation of epidermal growth factor receptor (EGFR) signaling contributes to diverse cancers. We used a proximity ligation assay (PLA) to detect EGFR in a complex with growth factor receptor-bound protein 2 (GRB2), the major signaling adaptor for EGFR. We used multiple lung cancer cell lines to develop and characterize EGFR:GRB2 PLA and correlated this assay with established biochemical measures of EGFR signaling. In a panel of patient-derived xenografts in mice, the intensity of EGFR:GRB2 PLA correlated with the reduction in tumor size in response to the EGFR inhibitor cetuximab. In tumor biopsies from three cohorts of lung cancer patients, positive EGFR:GRB2 PLA was observed in patients with and without EGFR mutations, and the intensity of EGFR:GRB2 PLA was predictive of overall survival in an EGFR inhibitor-treated cohort. Thus, we established the feasibility of using PLA to measure EGFR signaling-associated protein complexes in patient-based materials, suggesting the potential for similar assays for a broader array of receptor tyrosine kinases and other key signaling molecules.
Copyright © 2015, American Association for the Advancement of Science.
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15 MeSH Terms
Optimizing the sequence of anti-EGFR-targeted therapy in EGFR-mutant lung cancer.
Meador CB, Jin H, de Stanchina E, Nebhan CA, Pirazzoli V, Wang L, Lu P, Vuong H, Hutchinson KE, Jia P, Chen X, Eisenberg R, Ladanyi M, Politi K, Zhao Z, Lovly CM, Cross DA, Pao W
(2015) Mol Cancer Ther 14: 542-52
MeSH Terms: Acrylamides, Afatinib, Aged, Aniline Compounds, Animals, Antibodies, Monoclonal, Humanized, Cell Line, Tumor, Cell Proliferation, Cetuximab, Drug Resistance, Neoplasm, ErbB Receptors, Humans, Lung Neoplasms, Male, Mice, Nude, Molecular Targeted Therapy, Mutation, Quinazolines
Show Abstract · Added February 13, 2015
Metastatic EGFR-mutant lung cancers are sensitive to the first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib, and afatinib, but resistance develops. Acquired resistance to gefitinib or erlotinib occurs most commonly (>50%) via the emergence of a second-site EGFR mutation, T790M. Two strategies to overcome T790M-mediated resistance are dual inhibition of EGFR with afatinib plus the anti-EGFR antibody cetuximab (A+C), or mutant-specific EGFR inhibition with AZD9291. A+C and AZD9291 are now also being tested as first-line therapies, but whether these therapies will extend progression-free survival or induce more aggressive forms of resistance in this setting remains unknown. We modeled resistance to multiple generations of anti-EGFR therapies preclinically to understand the effects of sequential treatment with anti-EGFR agents on drug resistance and determine the optimal order of treatment. Using a panel of erlotinib/afatinib-resistant cells, including a novel patient-derived cell line (VP-2), we found that AZD9291 was more potent than A+C at inhibiting cell growth and EGFR signaling in this setting. Four of four xenograft-derived A+C-resistant cell lines displayed in vitro and in vivo sensitivity to AZD9291, but four of four AZD9291-resistant cell lines demonstrated cross-resistance to A+C. Addition of cetuximab to AZD9291 did not confer additive benefit in any preclinical disease setting. This work, emphasizing a mechanistic understanding of the effects of therapies on tumor evolution, provides a framework for future clinical trials testing different treatment sequences. This paradigm is applicable to other tumor types in which multiple generations of inhibitors are now available.
©2014 American Association for Cancer Research.
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18 MeSH Terms
3'-Deoxy-3'-[18F]-Fluorothymidine PET imaging reflects PI3K-mTOR-mediated pro-survival response to targeted therapy in colorectal cancer.
McKinley ET, Zhao P, Coffey RJ, Washington MK, Manning HC
(2014) PLoS One 9: e108193
MeSH Terms: Animals, Antineoplastic Agents, Cell Line, Tumor, Cetuximab, Colorectal Neoplasms, Mice, Mice, Nude, Phosphatidylinositol 3-Kinases, Positron-Emission Tomography, TOR Serine-Threonine Kinases
Show Abstract · Added January 23, 2015
Biomarkers that predict response to targeted therapy in oncology are an essential component of personalized medicine. In preclinical treatment response studies that featured models of wild-type KRAS or mutant BRAF colorectal cancer treated with either cetuximab or vemurafenib, respectively, we illustrate that [(18)F]-FLT PET, a non-invasive molecular imaging readout of thymidine salvage, closely reflects pro-survival responses to targeted therapy that are mediated by PI3K-mTOR activity. Activation of pro-survival mechanisms forms the basis of numerous modes of resistance. Therefore, we conclude that [(18)F]-FLT PET may serve a novel and potentially critical role to predict tumors that exhibit molecular features that tend to reflect recalcitrance to MAPK-targeted therapy. Though these studies focused on colorectal cancer, we envision that the results may be applicable to other solid tumors as well.
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10 MeSH Terms
Acquired resistance of EGFR-mutant lung adenocarcinomas to afatinib plus cetuximab is associated with activation of mTORC1.
Pirazzoli V, Nebhan C, Song X, Wurtz A, Walther Z, Cai G, Zhao Z, Jia P, de Stanchina E, Shapiro EM, Gale M, Yin R, Horn L, Carbone DP, Stephens PJ, Miller V, Gettinger S, Pao W, Politi K
(2014) Cell Rep 7: 999-1008
MeSH Terms: Adenocarcinoma, Adenocarcinoma of Lung, Afatinib, Animals, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, Cetuximab, Drug Resistance, Neoplasm, ErbB Receptors, Humans, Lung Neoplasms, Mechanistic Target of Rapamycin Complex 1, Mice, Mice, Nude, Mice, Transgenic, Multiprotein Complexes, Mutation, Quinazolines, Random Allocation, TOR Serine-Threonine Kinases, Xenograft Model Antitumor Assays
Show Abstract · Added May 27, 2014
Patients with EGFR-mutant lung adenocarcinomas (LUADs) who initially respond to first-generation tyrosine kinase inhibitors (TKIs) develop resistance to these drugs. A combination of the irreversible TKI afatinib and the EGFR antibody cetuximab can be used to overcome resistance to first-generation TKIs; however, resistance to this drug combination eventually emerges. We identified activation of the mTORC1 signaling pathway as a mechanism of resistance to dual inhibition of EGFR in mouse models. The addition of rapamycin reversed resistance in vivo. Analysis of afatinib-plus-cetuximab-resistant biopsy specimens revealed the presence of genomic alterations in genes that modulate mTORC1 signaling, including NF2 and TSC1. These findings pinpoint enhanced mTORC1 activation as a mechanism of resistance to afatinib plus cetuximab and identify genomic mechanisms that lead to activation of this pathway, revealing a potential therapeutic strategy for treating patients with resistance to these drugs.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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22 MeSH Terms
Nuclear epidermal growth factor receptor is a functional molecular target in triple-negative breast cancer.
Brand TM, Iida M, Dunn EF, Luthar N, Kostopoulos KT, Corrigan KL, Wleklinski MJ, Yang D, Wisinski KB, Salgia R, Wheeler DL
(2014) Mol Cancer Ther 13: 1356-68
MeSH Terms: Animals, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Cetuximab, Disease Models, Animal, Drug Resistance, Neoplasm, ErbB Receptors, Female, Gene Expression, Humans, Mice, Protein Transport, Signal Transduction, Triple Negative Breast Neoplasms, Xenograft Model Antitumor Assays, src-Family Kinases
Show Abstract · Added June 22, 2015
Triple-negative breast cancer (TNBC) is a subclass of breast cancers (i.e., estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) that have poor prognosis and very few identified molecular targets. Strikingly, a high percentage of TNBCs overexpresses the EGF receptor (EGFR), yet EGFR inhibition has yielded little clinical benefit. Over the last decade, advances in EGFR biology have established that EGFR functions in two distinct signaling pathways: (i) classical membrane-bound signaling and (ii) nuclear signaling. Previous studies have demonstrated that nuclear EGFR (nEGFR) can enhance resistance to anti-EGFR therapies and is correlated with poor overall survival in breast cancer. On the basis of these findings, we hypothesized that nEGFR may promote intrinsic resistance to cetuximab in TNBC. To examine this question, a battery of TNBC cell lines and human tumors were screened and found to express nEGFR. Knockdown of EGFR expression demonstrated that TNBC cell lines retained dependency on EGFR for proliferation, yet all cell lines were resistant to cetuximab. Furthermore, Src Family Kinases (SFKs) influenced nEGFR translocation in TNBC cell lines and in vivo tumor models, where inhibition of SFK activity led to potent reductions in nEGFR expression. Inhibition of nEGFR translocation led to a subsequent accumulation of EGFR on the plasma membrane, which greatly enhanced sensitivity of TNBC cells to cetuximab. Collectively, these data suggest that targeting both the nEGFR signaling pathway, through the inhibition of its nuclear transport, and the classical EGFR signaling pathway with cetuximab may be a viable approach for the treatment of patients with TNBC.
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19 MeSH Terms