scholarly journals Drug Resistance Mechanisms on Colorectal Cancer

2021 ◽  
Vol 5 (1 (January)) ◽  
pp. 88-93
Author(s):  
Hasan KURTER ◽  
Janberk YEŞİL ◽  
Ezgi DASKIN ◽  
Gizem ÇALIBAŞI KOÇAL ◽  
Hülya ELLİDOKUZ ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Resistance Mechanisms

scholarly journals Drug Resistance Mechanisms in Colorectal Cancer Dissected with Cell Type–Specific Dynamic Logic Models

2017 ◽  
Vol 77 (12) ◽  
pp. 3364-3375 ◽  
Author(s):  
Federica Eduati ◽  
Victoria Doldàn-Martelli ◽  
Bertram Klinger ◽  
Thomas Cokelaer ◽  
Anja Sieber ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Dynamic Logic ◽  
Resistance Mechanisms ◽  
Cell Type ◽  
Logic Models ◽  
Cell Type Specific

scholarly journals Bi-clustering based biological and clinical characterization of colorectal cancer in complementary to CMS classification

2018 ◽  
Author(s):  
Sha Cao ◽  
Wennan Chang ◽  
Changlin Wan ◽  
Yong Zhang ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Large Scale ◽  
Molecular Subtype ◽  
Resistance Mechanisms ◽  
Low Rank ◽  
Data Sets ◽  
Alternative Drug ◽  
Transcriptomics Data ◽  
Consensus Molecular Subtype

In light of the marked differences in the intrinsic biological underpinnings and prognostic outcomes among different subtypes, Consensus Molecular Subtype (CMS) classification provides a new taxonomy of colorectal cancer (CRC) solely based on transcriptomics data and has been accepted as a standard rule for CRC stratification. Even though CMS was built on highly cancer relevant features, it suffers from limitations in capturing the promiscuous mechanisms in a clinical setting. There are at least two facts about using transcriptomic data for prognosis prediction: the engagement of genes or pathways that execute the clinical response pathway are highly dynamic and interactive with others; and a predefined patient stratification not only largely decrease the statistical analysis power, but also excludes the fact that clusters of patients that confer similar clinical outcomes may or may not overlap with a pre-defined subgrouping. To enable a flexible and prospective stratified exploration, we here present a novel computational framework based on bi-clustering aiming to identify gene regulatory mechanisms associated with various biological, clinical and drug-resistance features, with full recognition of the transiency of transcriptional regulation and complicacies of patients subgrouping with regards to different biological and clinical settings. Our analysis on multiple large scale CRC transcriptomics data sets using a bi-clustering based formulation suggests that the detected local low rank modules can not only generate new biological understanding coherent to CMS stratification, but also identify predictive markers for prognosis that are general to CRC or CMS dependent, as well as novel alternative drug resistance mechanisms. Our key results include: (1) a comprehensive annotation of the local low rank module landscape of CRC; (2) a mechanistic relationship between different clinical subtypes and outcomes, as well as their characteristic biological underpinnings, visible through a novel consensus map; and (3) a few (novel) resistance mechanisms of Oxaliplatin, 5-Fluorouracil, and the FOLFOX therapy are revealed, some of which are validated on independent datasets.

scholarly journals Contribution of Genetic Variants of ATP Transporters (ABCC1 and ABCG2) genes with the Pathogenesis of Colorectal Cancer

2018 ◽  
Vol 15 (3) ◽  
pp. 555-559
Author(s):  
Huda A. Al Doghaither ◽  
Ayat B. Al-Ghafari
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Saudi Arabia ◽  
Genetic Variants ◽  
Metastatic Cancer ◽  
Resistance Mechanisms ◽  
Saudi Population ◽  
Chi Square ◽  
Poor Overall Survival ◽  
Acquired Drug Resistance

Colorectal cancer (CRC) is one of the major cancers that is characterized with high percentage of morbidity worldwide due to the advanced metastatic cancer that developed via acquired drug resistance mechanisms. Therefore, there is an urgent need to identify genetic variants in major genes that could contribute to the poor overall survival rate and drug-resistance. ATP-binding cassette (ABC) transporters are among the most studied genes that are related to the development of many cancers including CRC. In this study, three variants namely (G2168A and G3173A) in ABCC1 and (C421A) in ABCG2 were examined to evaluate their contribution to CRC in Saudi Arabia. DNA was extracted from the whole blood of 62 CRC patients and 100 controls. PCR-RFLP technique was used to identify the different genotypes among Saudi population. All statistical data were obtained by chi-square test and P values ˂0.05 were considered statistically significant. Interestingly, neither of the tested variants showed heterozygous nor homozygous distribution among the 162 samples. Therefore, those variants are rare in Saudi population and are not suspected to be involved in CRC pathogenesis. In conclusion, those variants cannot be used as diagnostic or prognostic markers for CRC in Saudi Arabia. However, more experiments need to be performed to confirm our findings.

scholarly journals Proteomic Analysis of miR-195 and miR-497 Replacement Reveals Potential Candidates that Increase Sensitivity to Oxaliplatin in MSI/P53wt Colorectal Cancer Cells

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1111 ◽  
Author(s):  
Poel ◽  
Boyd ◽  
Beekhof ◽  
Schelfhorst ◽  
Pham ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Cycle ◽  
Drug Resistance ◽  
Cell Viability ◽  
Proteomic Analysis ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Altered Expression ◽  
Transfected Cells ◽  
Viability Analysis

Most patients with advanced colorectal cancer (CRC) eventually develop resistance to systemic combination therapy. miR-195-5p and miR-497-5p are downregulated in CRC tissues and associated with drug resistance. Sensitization to 5-FU, oxaliplatin, and irinotecan by transfection with miR-195-5p and miR-497-5p mimics was studied using cell viability and clonogenic assays in cell lines HCT116, RKO, DLD-1, and SW480. In addition, proteomic analysis of transfected cells was implemented to identify potential targets. Significantly altered proteins were subjected to STRING (protein-protein interaction networks) database analysis to study the potential mechanisms of drug resistance. Cell viability analysis of transfected cells revealed increased sensitivity to oxaliplatin in microsatellite instable (MSI)/P53 wild-type HCT116 and RKO cells. HCT116 transfected cells formed significantly fewer colonies when treated with oxaliplatin. In sensitized cells, proteomic analysis showed 158 and 202 proteins with significantly altered expression after transfection with miR-195-5p and miR-497-5p mimics respectively, of which CHUK and LUZP1 proved to be coinciding downregulated proteins. Resistance mechanisms of these proteins may be associated with nuclear factor kappa-B signaling and G1 cell-cycle arrest. In conclusion, miR-195-5p and miR-497-5p replacement enhanced sensitivity to oxaliplatin in treatment naïve MSI/P53 wild-type CRC cells. Proteomic analysis revealed potential miRNA targets associated with the cell-cycle which possibly bare a relation with chemotherapy sensitivity.

A Critical Review of Second-generation anti-EGFR Monoclonal Antibodies in Metastatic Colorectal Cancer

2020 ◽  
Vol 21 ◽  
Author(s):  
Daniel Sur ◽  
Andrei Havasi ◽  
Alecsandra Gorzo ◽  
Claudia Burz
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Metastatic Colorectal Cancer ◽  
Second Generation ◽  
Current Data ◽  
Braf Mutations ◽  
Durable Response ◽  
Ongoing Research

Background: Anti-EGFR monoclonal antibodies (mAbs) have become a relevant solution for the treatment of patients with metastatic colorectal cancer. Current anti-EGFR monoclonal antibodies face a series of problems, including resistance and non-durable response, and RAS and BRAF mutations serve as exclusion criteria for treatment with anti-EGFR mAbs. Advances in molecular tumor profiling and information on subsequent pathways responsible for disease progression and drug resistance helped develop a new generation of anti-EGFR mAbs. These second-generation mAbs have been developed to overcome existing resistance mechanisms and to limit common side effects. For the moment, existing literature suggests that these novel anti-EGFR mAbs are far from finding their way to clinical practice soon. Objective: In this review, we summarize and evaluate current data regarding ongoing research and completed clinical trials for different second-generation anti-EGFR monoclonal antibodies. Conclusion: Anti-EGFR mAbs exhibit efficacy in advanced colorectal cancer, but second-generation mAbs failed to prove their benefit in the treatment of metastatic colorectal cancer. Understanding the biological basis of primary and acquired drug resistance could allow scientists to design better clinical trials and develop improved second-generation mAbs.

PI3K/ Akt/ mTOR Pathway as a Therapeutic Target for Colorectal Cancer: A Review of Preclinical and Clinical Evidence

2019 ◽  
Vol 20 (12) ◽  
pp. 1217-1226 ◽  
Author(s):  
Arunaksharan Narayanankutty
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Therapeutic Target ◽  
Clinical Evidence ◽  
Mtor Pathway ◽  
Colorectal Cancers ◽  
Patent Literature ◽  
Mtor Signalling ◽  
Natural And Synthetic

Background: Phosphoinositide 3-kinase (PI3Ks) is a member of intracellular lipid kinases and involved in the regulation of cellular proliferation, differentiation and survival. Overexpression of the PI3K/Akt/mTOR signalling has been reported in various forms of cancers, especially in colorectal cancers (CRC). Due to their significant roles in the initiation and progression events of colorectal cancer, they are recognized as a striking therapeutic target. Objective: The present review is aimed to provide a detailed outline on the role of PI3K/Akt/mTOR pathway in the initiation and progression events of colorectal cancers as well as its function in drug resistance. Further, the role of PI3K/Akt/mTOR inhibitors alone and in combination with other chemotherapeutic drugs, in alleviating colorectal cancer is also discussed. The review contains preclinical and clinical evidence as well as patent literature of the pathway inhibitors which are natural and synthetic in origin. Methods: The data were obtained from PubMed/Medline databases, Scopus and Google patent literature. Results: PI3K/Akt/mTOR signalling is an important event in colorectal carcinogenesis. In addition, it plays significant roles in acquiring drug resistance as well as metastatic initiation events of CRCs. Several small molecules of natural and synthetic origin have been found to be potent inhibitors of CRCs by effectively downregulating the pathway. Data from various clinical studies also support these pathway inhibitors and several among them are patented. Conclusion: Inhibitors of the PI3K/mTOR pathway have been successful for the treatment of primary and metastatic colorectal cancers, rendering the pathway as a promising clinical cancer therapeutic target.

Clinical applications of circulating tumor DNA in monitoring breast cancer drug resistance

2020 ◽  
Vol 16 (34) ◽  
pp. 2863-2878
Author(s):  
Yang Liu ◽  
Qian Du ◽  
Dan Sun ◽  
Ruiying Han ◽  
Mengmeng Teng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Clinical Applications ◽  
Current Status ◽  
Cancer Drug ◽  
Genomic Alteration ◽  
Tumor Dna

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Unfortunately, treatments often fail because of the development of drug resistance, the underlying mechanisms of which remain unclear. Circulating tumor DNA (ctDNA) is free DNA released into the blood by necrosis, apoptosis or direct secretion by tumor cells. In contrast to repeated, highly invasive tumor biopsies, ctDNA reflects all molecular alterations of tumors dynamically and captures both spatial and temporal tumor heterogeneity. Highly sensitive technologies, including personalized digital PCR and deep sequencing, make it possible to monitor response to therapies, predict drug resistance and tailor treatment regimens by identifying the genomic alteration profile of ctDNA, thereby achieving precision medicine. This review focuses on the current status of ctDNA biology, the technologies used to detect ctDNA and the potential clinical applications of identifying drug resistance mechanisms by detecting tumor-specific genomic alterations in breast cancer.

Dissecting the landscape of CAF-mediated drug resistance mechanisms in ALK-rearranged NSCLC

2020 ◽  
Vol 138 ◽  
pp. S48
Author(s):  
Q. Hu ◽  
L.L. Remsing Rix ◽  
X. Li ◽  
E.A. Welsh ◽  
B. Fang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Mechanisms
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