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EGFR Resistance Colon Cancer

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https://www.readbyqxmd.com/read/28685087/heterogeneity-in-the-colorectal-primary-tumor-and-the-synchronous-resected-liver-metastases-prior-to-and-after-treatment-with-an-anti-egfr-monoclonal-antibody
#1
Daniela Adua, Francesca Di Fabio, Giorgio Ercolani, Michelangelo Fiorentino, Elisa Gruppioni, Annalisa Altimari, Fabiola Lorena Rojas Limpe, Nicola Normanno, Antonio Daniele Pinna, Carmine Pinto
Molecular heterogeneity between primary tumors (PTs) and synchronous resected liver metastasis in colorectal cancer (CRC) has potential relevance in treatment strategies. Next-generation sequencing (NGS) may be able to increase the chances of identifying multiple molecular driver alterations, calling for therapy. The aim of the present study was to evaluate mutations in PT and synchronous resected liver metastases for patients with Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) exon 2 wild-type metastatic (m)CRC who underwent chemotherapy (CT) featuring an anti-epidermal growth factor receptor (EGFR) monoclonal antibody...
July 2017: Molecular and Clinical Oncology
https://www.readbyqxmd.com/read/28580315/coexistence-of-kras-and-braf-mutations-in-colorectal-cancer-a-case-report-supporting-the-concept-of-tumoral-heterogeneity
#2
Pegah Larki, Ehsan Gharib, Mohammad Yaghoob Taleghani, Fatemeh Khorshidi, Ehsan Nazemalhosseini-Mojarad, Hamid Asadzadeh Aghdaei
The detection of KRAS and BRAF mutations is a crucial step for the correct therapeutic approach and predicting the epidermal growth factor receptor (EGFR)-targeted therapy resistance of colorectal carcinomas. The concomitant KRAS and BRAF mutations occur rarely in the colorectal cancers (CRCs) with the prevalence of less than 0.001% of the cases. In patients with KRAS-mutant tumors, BRAF mutations should not regularly be tested unless the patient is participating in a clinical trial enriching for the presence of KRAS or BRAF-mutated tumor...
2017: Cell Journal
https://www.readbyqxmd.com/read/28408243/erlotinib-and-bevacizumab-in-patients-with-advanced-non-small-cell-lung-cancer-and-activating-egfr-mutations-belief-an-international-multicentre-single-arm-phase-2-trial
#3
Rafael Rosell, Urania Dafni, Enriqueta Felip, Alessandra Curioni-Fontecedro, Oliver Gautschi, Solange Peters, Bartomeu Massutí, Ramon Palmero, Santiago Ponce Aix, Enric Carcereny, Martin Früh, Miklos Pless, Sanjay Popat, Athanasios Kotsakis, Sinead Cuffe, Paolo Bidoli, Adolfo Favaretto, Patrizia Froesch, Noemí Reguart, Javier Puente, Linda Coate, Fabrice Barlesi, Daniel Rauch, Michael Thomas, Carlos Camps, Jose Gómez-Codina, Margarita Majem, Rut Porta, Riyaz Shah, Emer Hanrahan, Roswitha Kammler, Barbara Ruepp, Manuela Rabaglio, Marie Kassapian, Niki Karachaliou, Rachel Tam, David S Shames, Miguel A Molina-Vila, Rolf A Stahel
BACKGROUND: The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation...
May 2017: Lancet Respiratory Medicine
https://www.readbyqxmd.com/read/28404754/therapeutic-response-of-metastatic-colorectal-cancer-harboring-a-kras-missense-mutation-after-combination-chemotherapy-with-the-egfr-inhibitor-panitumumab
#4
Emil Lou, Donna D'Souza, Andrew C Nelson
Over the past decade, subset analyses of retrospective and prospective clinical studies have determined that KRAS-mutated metastatic colorectal cancers do not respond effectively to inhibition of epidermal growth factor receptor (EGFR) with the EGFR-targeting monoclonal antibodies cetuximab or panitumumab. Within the past few years, the scope of tested variants in the KRAS oncogene has expanded significantly, and testing of all RAS family genes has become more widely available in clinical laboratories. Expert consensus guidelines have recommended not using EGFR inhibitors in patients with KRAS-mutated tumors...
April 2017: Journal of the National Comprehensive Cancer Network: JNCCN
https://www.readbyqxmd.com/read/28220124/in-vivo-efficacy-of-umbilical-cord-blood-stem-cell-derived-nk-cells-in-the-treatment-of-metastatic-colorectal-cancer
#5
John P Veluchamy, Silvia Lopez-Lastra, Jan Spanholtz, Fenna Bohme, Nina Kok, Daniëlle A M Heideman, Henk M W Verheul, James P Di Santo, Tanja D de Gruijl, Hans J van der Vliet
Therapeutic monoclonal antibodies against the epidermal growth factor receptor (EGFR) act by inhibiting EGFR downstream signaling and by eliciting a natural killer (NK) cell-mediated antitumor response. The IgG1 mAb cetuximab has been used for treatment of RAS(wt) metastatic colorectal cancer (mCRC) patients, showing limited efficacy. In the present study, we address the potential of adoptive NK cell therapy to overcome these limitations investigating two allogeneic NK cell products, i.e., allogeneic activated peripheral blood NK cells (A-PBNK) and umbilical cord blood stem cell-derived NK cells (UCB-NK)...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28178681/molecular-profiling-of-metastatic-colorectal-tumors-using-next-generation-sequencing-a-single-institution-experience
#6
Jun Gong, May Cho, Marvin Sy, Ravi Salgia, Marwan Fakih
BACKGROUND: Recent molecular characterization of colorectal tumors has identified several molecular alterations of interest that are considered targetable in metastatic colorectal cancer (mCRC). METHODS: We conducted a single-institution, retrospective study based on comprehensive genomic profiling of tumors from 138 patients with mCRC using next-generation sequencing (NGS) via FoundationOne. RESULTS: Overall, RAS mutations were present in 51...
June 27, 2017: Oncotarget
https://www.readbyqxmd.com/read/28133136/-a-case-of-metastatic-colon-cancer-dramatically-affected-by-anti-egfr-antibody-therapy
#7
Ryoma Yagi, Yoshifumi Shimada, Kohei Miura, Yosuke Tajima, Takuma Okamura, Masato Nakano, Hiroshi Ichikawa, Masayuki Nagahashi, Jun Sakata, Takashi Kobayashi, Hitoshi Kameyama, Toshifumi Wakai, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii
RAS mutation is an established predictive biomarker of resistance to anti-epidermal growth factor receptor(EGFR)therapy in metastatic colorectal cancer. In addition, previous studies identified mutations in ERBB2, FGFR1, PDGFRA, BRAF, MAP2K1, PTEN, and PIK3CA as potential mechanisms of resistance to anti-EGFR therapy. Testing for these mutations might be necessary to determine eligibility for anti-EGFR therapy in patients with metastatic colorectal cancer. CancerPlex®is a nextgeneration sequencer for 413 cancer genes...
November 2016: Gan to Kagaku Ryoho. Cancer & Chemotherapy
https://www.readbyqxmd.com/read/28032592/feedback-activation-of-her3-attenuates-response-to-egfr-inhibitors-in-colon-cancer-cells
#8
Albert Bosch-Vilaró, Bart Jacobs, Valentina Pomella, Layka Abbasi Asbagh, Richard Kirkland, Joe Michel, Sharat Singh, Xinjun Liu, Phillip Kim, Gregory Weitsman, Paul R Barber, Borivoj Vojnovic, Tony Ng, Sabine Tejpar
The EGFR inhibitor cetuximab is approved for the treatment of colorectal cancer. However, both innate and acquired resistance mechanisms, including compensatory feedback loops, limit its efficacy. Nevertheless, the emergence of these feedback loops has remained largely unexplored to date. Here, we showed feedback upregulation of HER3 and induction of HER3 phosphorylation after cetuximab treatment in colon cancer cells. We also showed that this upregulation occurs, at least partly, through AKT inhibition. Together with this, we observed increased HER2:HER3 dimerization upon cetuximab treatment...
January 17, 2017: Oncotarget
https://www.readbyqxmd.com/read/28031175/adjuvant-folfox-cetuximab-in-full-ras-and-braf-wildtype-stage-iii-colon-cancer-patients
#9
RANDOMIZED CONTROLLED TRIAL
J Taieb, R Balogoun, K Le Malicot, J Tabernero, E Mini, G Folprecht, J-L Van Laethem, J-F Emile, C Mulot, S Fratté, C-B Levaché, L Saban-Roche, J Thaler, L N Petersen, J Bridgewater, G Perkins, C Lepage, E Van Cutsem, A Zaanan, P Laurent-Puig
Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research...
April 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27878272/mir-20b-reduces-5-fu-resistance-by-suppressing-the-adam9-egfr-signaling-pathway-in-colon-cancer
#10
Qiang Fu, Jing Cheng, Jindai Zhang, Yonglei Zhang, Xiaobing Chen, Suxia Luo, Jianguo Xie
Chemoresistance is a major obstacle to cancer therapy including that of colon cancer (CC). Although the dysregulation of many miRNAs has been implicated in 5-fluorouracil (5-FU) resistance in CC cells, the specific role of miR-20b in chemoresistance has not been documented. In the present study, we first determined the expression of miR-20b by RT-PCR and the levels of a disintegrin and metalloprotease 9 (ADAM9) and epidermal growth factor receptor (EGFR) by western blotting in CC and adjacent non-cancerous tissues from 5-FU-sensitive or -resistant CC patients...
January 2017: Oncology Reports
https://www.readbyqxmd.com/read/27708224/a-module-of-inflammatory-cytokines-defines-resistance-of-colorectal-cancer-to-egfr-inhibitors
#11
Valerio Gelfo, Maria Teresa Rodia, Michela Pucci, Massimiliano Dall'Ora, Spartaco Santi, Rossella Solmi, Lee Roth, Moshit Lindzen, Massimiliano Bonafè, Andrea Bertotti, Elisabetta Caramelli, Pier-Luigi Lollini, Livio Trusolino, Yosef Yarden, Gabriele D'Uva, Mattia Lauriola
Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted. Cetuximab, one of the monoclonal antibodies targeting this pathway, is employed to treat patients with colorectal cancer. However, many patients are intrinsically refractory to this treatment, and those who respond develop secondary resistance along time. Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes...
November 1, 2016: Oncotarget
https://www.readbyqxmd.com/read/27603596/tunicamycin-enhances-human-colon-cancer-cells-to-trail-induced-apoptosis-by-jnk-chop-mediated-dr5-upregulation-and-the-inhibition-of-the-egfr-pathway
#12
Xiaoqing Guo, Yue Meng, Xiaotong Sheng, Yuan Guan, Fenglei Zhang, Zhen Han, Yuying Kang, Guihua Tai, Yifa Zhou, Hairong Cheng
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) is a cytokine that selectively induces apoptosis in many tumor cells while leaving normal cells intact and is thus an attractive candidate for antitumor therapies. This paper reports that the combination of tunicamycin plus TRAIL produced a strong synergistic effect in TRAIL-sensitive human colon cancer HCT116 cells and TRAIL-resistant HT-29 cells. On a cellular mechanistic level, tunicamycin-enhanced TRAIL-induced apoptosis by death receptor (DR) 5 upregulation and DR4 deglycosylation...
January 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/27556359/dual-targeting-of-her3-and-mek-may-overcome-her3-dependent-drug-resistance-of-colon-cancers
#13
Giulia Bon, Rossella Loria, Carla Azzurra Amoreo, Alessandra Verdina, Isabella Sperduti, Arianna Mastrofrancesco, Silvia Soddu, Maria Grazia Diodoro, Marcella Mottolese, Matilde Todaro, Giorgio Stassi, Michele Milella, Ruggero De Maria, Rita Falcioni
Although the medical treatment of colorectal cancer has evolved greatly in the last years, a significant portion of early-stage patients develops recurrence after therapies. The current clinical trials are directed to evaluate new drug combinations and treatment schedules. By the use of patient-derived or established colon cancer cell lines, we found that the tyrosine kinase receptor HER3 is involved in the mechanisms of resistance to therapies. In agreement, the immunohistochemical analysis of total and phospho-HER3 expression in 185 colorectal cancer specimens revealed a significant correlation with lower disease-free survival...
August 19, 2016: Oncotarget
https://www.readbyqxmd.com/read/27399917/expression-of-the-chemokine-cxcl14-and-cetuximab-dependent-tumour-suppression-in-head-and-neck-squamous-cell-carcinoma
#14
T Kondo, S Ozawa, T Ikoma, X-Y Yang, K Kanamori, K Suzuki, H Iwabuchi, Y Maehata, C Miyamoto, T Taguchi, T Kiyono, E Kubota, R-I Hata
Cetuximab, a monoclonal antibody against the epidermal growth factor receptor (EGFR), has been successfully used to treat some patients with colorectal cancer and those with head and neck squamous cell carcinoma (HNSCC). For the effective treatment, it is essential to first identify cetuximab-responsive patients. The level of EGFR expression and/or the presence of mutations in signalling molecules downstream of the EGFR pathway have been reported to be determining factors for cetuximab responsiveness in colorectal cancer patients; however, limited data have been reported for HNSCC patients...
July 11, 2016: Oncogenesis
https://www.readbyqxmd.com/read/27332557/therapeutic-strategies-in-diseases-of-the-digestive-tract-2015-and-beyond-targeted-therapies-in-colon-cancer-today-and-tomorrow
#15
Michael Pohl, Wolff Schmiegel
BACKGROUND: Colorectal cancer (CRC) is the third most common cancer type in Western countries. Significant progress has been made in the last decade in the therapy of metastatic CRC (mCRC) with a median overall survival (OS) of patients exceeding 30 months. The integration of biologic targeted therapies and anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MABs) in the treatment of patients with genomically selected all-RAS wild-type mCRC leads to a significant progress in advanced incurable disease state...
2016: Digestive Diseases
https://www.readbyqxmd.com/read/27328312/fat1-a-potential-target-for-monoclonal-antibody-therapy-in-colon-cancer
#16
Piero Pileri, Susanna Campagnoli, Alberto Grandi, Matteo Parri, Elisa De Camilli, Chaojun Song, Luisa Ganfini, Aurelien Lacombe, Ilaria Naldi, Paolo Sarmientos, Caterina Cinti, Boquan Jin, Guido Grandi, Giuseppe Viale, Luigi Terracciano, Renata Grifantini
BACKGROUND: Colorectal cancer (CRC) is one of the major causes of cancer-associated mortality worldwide. The currently approved therapeutic agents have limited efficacy. METHODS: The atypical cadherin FAT1 was discovered as a novel CRC-associated protein by using a monoclonal antibody (mAb198.3). FAT1 expression was assessed in CRC cells by immunohistochemistry (IHC), immunoblots, flow cytometry and confocal microscopy. In addition, in vitro and in vivo tumour models were done to assess FAT1 potential value for therapeutic applications...
June 28, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/27121209/targeted-sequencing-identifies-genetic-alterations-that-confer-primary-resistance-to-egfr-tyrosine-kinase-inhibitor-korean-lung-cancer-consortium
#17
Sun Min Lim, Hye Ryun Kim, Eun Kyung Cho, Young Joo Min, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Byoung Chul Cho, Ji-Hyun Lee, Hye Cheol Jeong, Eun Kyung Kim, Joo-Hang Kim
BACKGROUND: Non-small-cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations may exhibit primary resistance to EGFR tyrosine kinase inhibitor (TKI). We aimed to examine genomic alterations associated with de novo resistance to gefitinib in a prospective study of NSCLC patients. Patients and methods: One-hundred and fifty two patients with activating EGFR mutations were included in this study and 136 patients' tumor sample were available for targeted sequencing of genomic alterations in 22 genes using the Colon and Lung Cancer panel (Ampliseq, Life Technologies)...
June 14, 2016: Oncotarget
https://www.readbyqxmd.com/read/27121052/inhibition-of-pro-hgf-activation-by-sri31215-a-novel-approach-to-block-oncogenic-hgf-met-signaling
#18
Benjamin Y Owusu, Namita Bansal, Phanindra K M Venukadasula, Larry J Ross, Troy E Messick, Sanjay Goel, Robert A Galemmo, Lidija Klampfer
The binding of hepatocyte growth factor (HGF) to its receptor MET activates a signaling cascade that promotes cell survival, proliferation, cell scattering, migration and invasion of malignant cells. HGF is secreted by cancer cells or by tumor-associated fibroblasts as pro-HGF, an inactive precursor. A key step in the regulation of HGF/MET signaling is proteolytic processing of pro-HGF to its active form by one of the three serine proteases, matriptase, hepsin or HGF activator (HGFA).We developed SRI 31215, a small molecule that acts as a triplex inhibitor of matriptase, hepsin and HGFA and mimics the activity of HAI-1/2, endogenous inhibitors of HGF activation...
May 17, 2016: Oncotarget
https://www.readbyqxmd.com/read/27060453/inhibition-of-nf-%C3%AE%C2%BAb-and-metastasis-in-irinotecan-cpt-11-resistant-lovo-colon-cancer-cells-by-thymoquinone-via-jnk-and-p38
#19
Ming-Cheng Chen, Nien-Hung Lee, Hsi-Hsien Hsu, Tsung-Jung Ho, Chuan-Chou Tu, Ray-Jade Chen, Yueh-Min Lin, Vijaya Padma Viswanadha, Wei-Wen Kuo, Chih-Yang Huang
Clinically used chemotherapeutics can effectively eliminate most tumor cells. However, they cause unwanted side effects and result in chemoresistance. To overcome such problems, phytochemicals are now used to treat cancers by means of targeted therapy. Thymoquinone (TQ) is used to treat different cancers (including colon cancer) and is an NF-κB inhibitor. Irinotecan resistant (CPT-11-R) LoVo colon cancer cell line was previous constructed by step-wise CPT-11 challenges to un-treated parental LoVo cells and expresses EGFR/IKKα/β/NF-κB pathway...
February 2017: Environmental Toxicology
https://www.readbyqxmd.com/read/27039744/distribution-of-kras-and-braf-mutations-in-metastatic-colorectal-cancers-in-turkish-patients
#20
Orhan Gorukmez, Tahsin Yakut, Ozlem Gorukmez, Sebnem Ozemri Sag, Mutlu Karkucak, Ozkan Kanat
The results of this study demonstrate the potential prognostic and predictive values of KRAS and BRAF gene mutations in patients with colorectal cancer (CRC). It has been proven that KRAS and BRAF mutations are predictive biomarkers for resistance to anti-EGFR monoclonal antibody treatment in patients with metastatic CRC (mCRC). We demonstrated the distribution of KRAS (codons 12, 13 and 61) and BRAF (codon 600) gene mutations in 50 mCRCs using direct sequencing and compared the results with clinicopathological data...
2016: Asian Pacific Journal of Cancer Prevention: APJCP
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