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https://www.readbyqxmd.com/read/28073102/cancer-resistance-to-therapies-against-the-egfr-ras-raf-pathway-the-role-of-mek
#1
REVIEW
Erika Martinelli, Floriana Morgillo, Teresa Troiani, Fortunato Ciardiello
The mitogen-activated protein kinases (MAPKs) mediate intracellular signals activated by a wide variety of extracellular stimuli. The activation of the RAS-RAF-MEK-MAPK cascade culminates in the regulation of gene transcription promoting cancer cell proliferation, survival, migration and angiogenesis. MEK (mitogen-activated protein kinase kinase-MAPKK) 1/2 is a transducer of the growth factor receptor-RAS-RAF-MAPK signalling cascade and plays a relevant role in development and progression of human cancers, such as colorectal cancer (CRC), non small cell lung cancer (NSCLC)...
December 30, 2016: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28068936/retrospective-study-of-ras-pik3ca-braf-tumor-mutations-as-predictors-of-response-to-first-line-chemotherapy-with-bevacizumab-in-metastatic-colorectal-cancer-patients
#2
Izuma Nakayama, Eiji Shinozaki, Tomohiro Matsushima, Takeru Wakatsuki, Mariko Ogura, Takashi Ichimura, Masato Ozaka, Daisuke Takahari, Mitsukuni Suenaga, Keisho Chin, Nobuyuki Mizunuma, Kensei Yamaguchi
BACKGROUND: After analysis of minor RAS mutations (KRAS exon 3, 4/NRAS) in the FIRE-3 and PRIME studies, an expanded range of RAS mutations were established as a negative predictive marker for the efficacy of anti-EGFR antibody treatment. BRAF and PIK3CA mutations may be candidate biomarkers for anti-EGFR targeted therapies. However, it remains unknown whether RAS/PIK3CA/BRAF tumor mutations can predict the efficacy of bevacizumab in metastatic colorectal cancer. We assessed whether selection according to RAS/PIK3CA/BRAF mutational status could be beneficial for patients treated with bevacizumab as first-line treatment for metastatic colorectal cancer...
January 9, 2017: BMC Cancer
https://www.readbyqxmd.com/read/28058585/detection-of-kras-mutations-in-plasma-dna-using-a-fully-automated-rapid-detection-system-in-colorectal-cancer-patients
#3
Kazuhisa Hosoya, Satoshi Matsusaka, Tomomi Kashiwada, Koichi Suzuki, Norio Ureshino, Akemi Sato, Yoshio Miki, Kazuki Kitera, Mitsuharu Hirai, Kiyohiko Hatake, Shinya Kimura, Naoko Sueoka-Aragane
KRAS mutations have been recognized as predictive markers of primary resistance to anti-EGFR-antibodies in colorectal cancer patients. In addition, newly detected KRAS mutations have been reported to be related with acquired resistance to chemotherapy containing anti-EGFR antibody. Considering this evidence, monitoring of KRAS mutations is indispensable for making treatment decisions, and the method should be non-invasive allowing repeated examinations. Recently, we established a novel automated sensitive detection system for KRAS mutations, named mutation-biased PCR quenching probe system (MBP-QP)...
January 5, 2017: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28055269/targeting-pd-1-pathway-a-new-hope-for-gastrointestinal-cancers
#4
Burak Bilgin, Mehmet An Sendur, Muhammed Bülent Akıncı, Didem Şener Dede, Bülent Yalçın
BACKGROUND: VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most of the Gastrointestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. In this review article, we aimed to discuss the efficacy and safety of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in the era of published or reported recent studies...
January 5, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28045335/phase-ii-trial-of-capecitabine-plus-erlotinib-versus-capecitabine-alone-in-patients-with-advanced-colorectal-cancer
#5
Mark D Vincent, Daniel Breadner, Denis Soulieres, Ian G Kerr, Michael Sanatani, Walter Kocha, Peter Klimo, Mary J MacKenzie, Anne O'Connell, Frances Whiston, Anne S Malpage, Larry Stitt, Stephen A Welch
: Aim & methods: Capecitabine monotherapy as palliation for advanced colorectal cancer (CRC) is generally well tolerated. Adding erlotinib, an EGFR-tyrosine kinase inhibitor, might improve efficacy versus capecitabine alone. 82 patients received capecitabine alone (Arm 1) or capecitabine with erlotinib (Arm 2). RESULTS: Median time-to-progression (TTP) in Arm 1 was 7.9 months versus 9.2 in Arm 2. In KRAS-wild type (WT) patients TTP was 8.4 and 11.7 months in Arms 1 and 2, respectively...
January 3, 2017: Future Oncology
https://www.readbyqxmd.com/read/28044264/clinicopathological-associations-of-k-ras-and-n-ras-mutations-in-indonesian-colorectal-cancer-cohort
#6
Michael Levi, Gintang Prayogi, Farid Sastranagara, Edi Sudianto, Grace Widjajahakim, Winiarti Gani, Albert Mahanadi, Jocelyn Agnes, Bela Haifa Khairunisa, Ahmad R Utomo
BACKGROUND: K-RAS and recently N-RAS gene mutation testing are mandatory requirements prior to anti-epidermal growth factor receptor (EGFR) monoclonal antibody treatment of metastatic CRC. Mutation prevalence and distribution in Indonesian colorectal cancer (CRC) are not known. METHODS: Combined methods of PCR high-resolution melt (HRM), restriction fragment length polymorphism (RFLP), and direct DNA sequencing were used to genotype exons 2, 3, and 4 of both K-RAS and N-RAS genes for routine clinical testing of CRC patients...
January 3, 2017: Journal of Gastrointestinal Cancer
https://www.readbyqxmd.com/read/28032593/the-impact-of-co-expression-of-wild-type-egfr-and-its-ligands-determined-by-immunohistochemistry-for-response-to-treatment-with-cetuximab-in-patients-with-metastatic-colorectal-cancer
#7
Said Khelwatty, Sharadah Essapen, Izhar Bagwan, Margaret Green, Alan Seddon, Helmout Modjtahedi
Anti-EGFR mAbs cetuximab and panitumumab are routinely used for the treatment of patients with KRAS-wild type metastatic colorectal cancer (mCRC). However, in some patients their efficacy remains modest and with no clear association between the EGFR protein expression determined by PharmDx™ kit, and response to anti-EGFR therapies. Therefore, we investigated the relative expression and predictive value of wild-type EGFR (wtEGFR), mutated EGFRvIII and EGFR ligand proteins in mCRC patients treated with cetuximab...
December 9, 2016: Oncotarget
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...
December 9, 2016: Oncotarget
https://www.readbyqxmd.com/read/28028983/monitoring-of-circulating-tumor-cells-by-a-combination-of-immunomagnetic-enrichment-and-rt-pcr-in-colorectal-cancer-patients-undergoing-surgery
#9
Gabriela Vojtechova, Lucie Benesova, Barbora Belsanova, Petra Minarikova, Miroslav Levy, Ludmila Lipska, Stepan Suchanek, Miroslav Zavoral, Marek Minarik
BACKGROUND: The presence of circulating tumor cells (CTC) has been reported in patients with advanced colorectal cancer. Monitoring CTC (also known as a liquid-biopsy) has recently become the center of interest for low-invasive monitoring of cancer progression and predictive biomarkers testing. Along with high-cost technology and a complex methodology, a straightforward method based on magnetic beads enrichment followed by RT-PCR is set to allow for routine CTC analysis in colorectal cancer patients...
November 2016: Advances in Clinical and Experimental Medicine: Official Organ Wroclaw Medical University
https://www.readbyqxmd.com/read/28025786/egfr-gene-amplification-and-kras-mutation-predict-response-to-combination-targeted-therapy-in-metastatic-colorectal-cancer
#10
Sajid A Khan, Zhaoshi Zeng, Jinru Shia, Philip B Paty
Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified...
December 26, 2016: Pathology Oncology Research: POR
https://www.readbyqxmd.com/read/28025473/-target-therapy-in-unresectable-or-metastatic-colorectal-cancer
#11
REVIEW
Jae Hyun Kim, Seun Ja Park
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in Korea. Despite recent developments in the treatment of CRC, the median overall survival time in patients with metastatic CRC is less than 30 months. The biologic agents that target the epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have proven clinical benefits in the treatment of patient with metastatic CRC. Anti-EGFR agents, including cetuximab and panitumumab, as well as anti-VEGF agents, including bevacizumab, aflibercept, ramucirumab, and regorafenib have been shown to extend survival in combination with cytotoxic chemotherapy...
December 25, 2016: Korean Journal of Gastroenterology, Taehan Sohwagi Hakhoe Chi
https://www.readbyqxmd.com/read/28005260/high-early-growth-response-1-egr1-expression-correlates-with-resistance-to-anti-egfr-treatment-in-vitro-and-with-poorer-outcome-in-metastatic-colorectal-cancer-patients-treated-with-cetuximab
#12
S S Kumar, Y Tomita, J Wrin, M Bruhn, A Swalling, M Mohammed, T J Price, J E Hardingham
PURPOSE: Biomarkers, such as mutant RAS, predict resistance to anti-EGFR therapy in only a proportion of patients, and hence, other predictive biomarkers are needed. The aims were to identify candidate genes upregulated in colorectal cancer cell lines resistant to anti-EGFR monoclonal antibody treatment, to knockdown (KD) these genes in the resistant cell lines to determine if sensitivity to anti-EGFR antibody was restored, and finally to perform a pilot correlative study of EGR1 expression and outcomes in a cohort of metastatic colorectal cancer (mCRC) patients given cetuximab therapy...
December 22, 2016: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/28002810/mechanisms-of-resistance-to-anti-egfr-therapy-in-colorectal-cancer
#13
REVIEW
Ben Zhao, Lu Wang, Hong Qiu, Mingsheng Zhang, Li Sun, Ping Peng, Qianqian Yu, Xianglin Yuan
Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy is effective for patients with RAS wild type metastatic colorectal cancer (mCRC). However, only a small percentage of mCRC patients are sensitive to anti-EGFR therapy and even the best cases finally become refractory to this therapy. It has become apparent that the RAS mutations correlate with resistance to anti-EGFR therapy. However, these resistance mechanisms only account for nearly 35% to 50% of nonresponsive patients, suggesting that there might be additional mechanisms...
December 18, 2016: Oncotarget
https://www.readbyqxmd.com/read/28000889/high-concordance-rate-of-kras-braf-mutations-and-msi-h-between-primary-colorectal-cancer-and-corresponding-metastases
#14
Kenji Fujiyoshi, Gou Yamamoto, Akemi Takahashi, Yoshiko Arai, Mina Yamada, Miho Kakuta, Kensei Yamaguchi, Yoshito Akagi, Yoji Nishimura, Hirohiko Sakamoto, Kiwamu Akagi
Genetic testing is needed for the treatment of colorectal cancer (CRC), especially molecular-targeted therapy. The effects of anti-EGFR therapy and prognosis are affected by the presence of KRAS mutations. However, whether primary CRC or metastatic tissues are appropriate in the analysis is still unclear. In the present study, we assessed the concordance of KRAS/BRAF mutation status and microsatellite instability (MSI) in primary CRC and corresponding metastases. This study enrolled 457 patients with surgically resected primary and corresponding metastatic CRC (499 synchronous metastases and 57 metachronous metastases) and seven local recurrences, and KRAS/BRAF mutation and MSI status were analysed for these tumours...
December 15, 2016: Oncology Reports
https://www.readbyqxmd.com/read/27999270/clinical-application-of-targeted-next-generation-sequencing-for-colorectal-cancers
#15
REVIEW
Quitterie Fontanges, Ricardo De Mendonca, Isabelle Salmon, Marie Le Mercier, Nicky D'Haene
Promising targeted therapy and personalized medicine are making molecular profiling of tumours a priority. For colorectal cancer (CRC) patients, international guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-epidermal growth factor receptor agents (anti-EGFR). Daily, new data emerge on the theranostic and prognostic role of molecular biomarkers, which is a strong incentive for a validated, sensitive and broadly available molecular screening test in order to implement and improve multi-modal therapy strategy and clinical trials...
December 16, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27995091/recent-advances-in-chemotherapy-and-surgery-for-colorectal-liver-metastases
#16
REVIEW
Guillaume Passot, Olivier Soubrane, Felice Giuliante, Giuseppe Zimmitti, Diane Goéré, Suguru Yamashita, Jean-Nicolas Vauthey
BACKGROUND: The liver is the most common site of metastases for colorectal cancer, and combined resection with systemic chemotherapy is the most effective strategy for survival. The aim of this article is to provide a comprehensive summary on four hot topics related to chemotherapy and surgery for colorectal liver metastases (CLM), namely: (1) chemotherapy-related liver injuries: prediction and impact, (2) surgery for initially unresectable CLM, (3) the emerging role of RAS mutations, and (4) the role of hepatic arterial infusion of chemotherapy (HAIC)...
November 2016: Liver Cancer
https://www.readbyqxmd.com/read/27994592/kir-genes-and-their-ligands-predict-the-response-to-anti-egfr-monoclonal-antibodies-in-solid-tumors
#17
Cristina Morales-Estevez, Juan De la Haba-Rodriguez, Barbara Manzanares-Martin, Ignacio Porras-Quintela, Antonio Rodriguez-Ariza, Alberto Moreno-Vega, Maria J Ortiz-Morales, Maria A Gomez-España, Maria T Cano-Osuna, Javier Lopez-Gonzalez, Beatriz Chia-Delgado, Rafael Gonzalez-Fernandez, Enrique Aranda-Aguilar
Killer-cell immunoglobulin-like receptors (KIRs) regulate the killing function of natural killer cells, which play an important role in the antibody-dependent cell-mediated cytotoxicity response exerted by therapeutic monoclonal antibodies (mAbs). However, it is unknown whether the extensive genetic variability of KIR genes and/or their human leukocyte antigen (HLA) ligands might influence the response to these treatments. This study aimed to explore whether the variability in KIR/HLA genes may be associated with the variable response observed to mAbs based anti-epidermal growth factor receptor (EGFR) therapies...
2016: Frontiers in Immunology
https://www.readbyqxmd.com/read/27965461/kras-mutant-colorectal-cancer-gene-signatures-identified-angiotensin-ii-receptor-blockers-as-potential-therapies
#18
Qing Wen, Philip D Dunne, Paul G O'Reilly, Gerald Li, Anthony J Bjourson, Darragh G McArt, Peter W Hamilton, Shu-Dong Zhang
Colorectal cancer (CRC) is a life-threatening disease with high prevalence and mortality worldwide. The KRAS oncogene is mutated in approximately 40% of CRCs. While antibody based EGFR inhibitors (cetuximab and panitumumab) represent a major treatment strategy for advanced KRAS wild type (KRAS-WT) CRCs, there still remains no effective therapeutic course for advanced KRAS mutant (KRAS-MT) CRC patients.In this study, we employed a novel and comprehensive approach of gene expression connectivity mapping (GECM) to identify candidate compounds to target KRAS-MT tumors...
December 10, 2016: Oncotarget
https://www.readbyqxmd.com/read/27959384/pro-metastatic-intracellular-signaling-of-the-elaidic-trans-fatty-acid
#19
Kiyomu Fujii, Yi Luo, Rina Fujiwara-Tani, Shingo Kishi, Song He, Shuyun Yang, Takamitsu Sasaki, Hitoshi Ohmori, Hiroki Kuniyasu
Trans fatty acids (TFAs) are risk factors of cardiovascular disorders, and a few studies have reported the cancer-promoting effects of TFAs. In the present study, we examined the effects and signaling of elaidic acid (EA), a TFA, in colorectal cancer (CRC) cells. Oral intake of EA increased the metastasis of CT26 mouse CRC cells by inducing the expression of stemness markers nucleostemin (NS) and CD133. Mechanisms underlying EA-induced signaling were confirmed by determining the binding of EA to G-protein coupled receptor 40 (GPR40) and GPR120 by performing surface protein internalization assay...
January 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/27929064/acquired-ras-or-egfr-mutations-and-duration-of-response-to-egfr-blockade-in-colorectal-cancer
#20
Beth O Van Emburgh, Sabrina Arena, Giulia Siravegna, Luca Lazzari, Giovanni Crisafulli, Giorgio Corti, Benedetta Mussolin, Federica Baldi, Michela Buscarino, Alice Bartolini, Emanuele Valtorta, Joana Vidal, Beatriz Bellosillo, Giovanni Germano, Filippo Pietrantonio, Agostino Ponzetti, Joan Albanell, Salvatore Siena, Andrea Sartore-Bianchi, Federica Di Nicolantonio, Clara Montagut, Alberto Bardelli
Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival...
December 8, 2016: Nature Communications
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