scholarly journals Targeting Receptor Kinases in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 433 ◽  
Author(s):  
Marilina García-Aranda ◽  
Maximino Redondo
Keyword(s):  
Colorectal Cancer ◽  
Cancer Treatment ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Great Effort ◽  
Screening Programs ◽  
Common Cancer ◽  
Receptor Kinases ◽  
Common Malignancy

Colorectal cancer is the third most common malignancy in men and the second most common cancer in women. Despite the success of screening programs and the development of adjuvant therapies, the global burden of colorectal cancer is expected to increase by 60% to more than 2.2 million new cases and 1.1 million deaths by 2030. In recent years, a great effort has been made to demonstrate the utility of protein kinase inhibitors for cancer treatment. Considering this heterogeneous disease is defined by mutations that activate different Receptor Tyrosine Kinases (RTKs) and affect downstream components of RTK-activated transduction pathways, in this review we analyze the potential utility of different kinase inhibitors for colorectal cancer treatment.

scholarly journals Identification of Two Kinase Inhibitors with Synergistic Toxicity with Low-Dose Hydrogen Peroxide in Colorectal Cancer Cells In vitro

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 122 ◽  
Author(s):  
Eric Freund ◽  
Kim-Rouven Liedtke ◽  
Lea Miebach ◽  
Kristian Wende ◽  
Amanda Heidecke ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Colorectal Cancer ◽  
Hydrogen Peroxide ◽  
Protein Kinase ◽  
Tumor Cells ◽  
Low Dose ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Colorectal Cancer Cells

Colorectal carcinoma is among the most common types of cancers. With this disease, diffuse scattering in the abdominal area (peritoneal carcinosis) often occurs before diagnosis, making surgical removal of the entire malignant tissue impossible due to a large number of tumor nodules. Previous treatment options include radiation and its combination with intraperitoneal heat-induced chemotherapy (HIPEC). Both options have strong side effects and are often poor in therapeutic efficacy. Tumor cells often grow and proliferate dysregulated, with enzymes of the protein kinase family often playing a crucial role. The present study investigated whether a combination of protein kinase inhibitors and low-dose induction of oxidative stress (using hydrogen peroxide, H2O2) has an additive cytotoxic effect on murine, colorectal tumor cells (CT26). Protein kinase inhibitors from a library of 80 substances were used to investigate colorectal cancer cells for their activity, morphology, and immunogenicity (immunogenic cancer cell death, ICD) upon mono or combination. Toxic compounds identified in 2D cultures were confirmed in 3D cultures, and additive cytotoxicity was identified for the substances lavendustin A, GF109203X, and rapamycin. Toxicity was concomitant with cell cycle arrest, but except HMGB1, no increased expression of immunogenic markers was identified with the combination treatment. The results were validated for GF109203X and rapamycin but not lavendustin A in the 3D model of different colorectal (HT29, SW480) and pancreatic cancer cell lines (MiaPaca, Panc01). In conclusion, our in vitro data suggest that combining oxidative stress with chemotherapy would be conceivable to enhance antitumor efficacy in HIPEC.

Projection of cancer incidence and death to 2040 in the US: Impact of cancer screening and a changing demographic.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1566-1566 ◽  
Author(s):  
Lola Rahib ◽  
Mackenzie Wehner ◽  
Lynn McCormick Matrisian ◽  
Kevin Thomas Nead
Keyword(s):  
Breast Cancer ◽  
Colorectal Cancer ◽  
Lung Cancer ◽  
Cancer Screening ◽  
Cancer Incidence ◽  
Intrahepatic Bile Duct ◽  
Death Rates ◽  
Screening Programs ◽  
Common Cancer ◽  
The Us

1566 Background: Coping with the current and future burden of cancer requires an in-depth understanding of cancer incidence and death trends. As of 2020, breast, lung, prostate, and colorectal cancer are the most incident cancers, while lung, colorectal, pancreas, and breast cancer result in the most deaths. Here we integrate observed cancer statistics and trends with observed and estimated US demographic data to project cancer incidences and deaths to the year 2040. Methods: Demographic cancer-specific delay-adjusted incidence and death rates from the Surveillance, Epidemiology, and End Results Program (2014-2016) were combined with US Census Bureau population growth projections (2016) and average annual percentage changes in incidence (2011-2015) and death (2012-2016) rates to project cancer incidences and deaths through the year 2040. We examined the 10 most incident and deadly cancers as of 2020. We utilized Joinpoint analysis to examine changes in incidence and death rates over time relative to changes in screening guidelines. Results: We predict the most incident cancers in 2040 in the US will be breast (322,000 diagnoses in 2040) and lung (182,000 diagnoses in 2040) cancer. Continuing decades long observed incident rate trends we predict that melanoma (173,000 diagnoses in 2040) will become the 3rd most common cancer while prostate cancer (63,000 diagnoses in 2040) will become the 5th most common cancer after colorectal cancer (139,000 diagnoses in 2040). Lung cancer (61,000 deaths in 2040) is predicted to continue to be the leading cause of cancer related death, with pancreas (45,000 deaths in 2040) and liver & intrahepatic bile duct (38,000 deaths in 2040) cancer surpassing colorectal cancer (34,000 deaths in 2040) to become the second and third most common causes of cancer related death, respectively. Breast cancer deaths (29,000 in 2040) are predicted to continue to decrease and become the fifth most common cause of cancer death. Joinpoint analysis of incidence and death rates supports a significant past, present, and future impact of cancer screening programs on the number of cancer diagnoses and deaths, particularly for prostate, thyroid, melanoma incidences, and lung cancer deaths. Conclusions: We demonstrate marked changes in the predicted landscape of cancer incidence and deaths by 2040. Our analysis reveals an influence of cancer screening programs on the number of cancer diagnoses and deaths in future years. These projections are important to guide future research funding allocations, healthcare planning, and health policy efforts.

scholarly journals Therapeutic Drug Monitoring of Protein Kinase Inhibitors in Breast Cancer Patients

2021 ◽  
Vol 122 (4) ◽  
pp. 243-256
Author(s):  
Jaroslava Roušarová ◽  
Martin Šíma ◽  
Ondřej Slanař
Keyword(s):  
Breast Cancer ◽  
Protein Kinase ◽  
Therapeutic Drug Monitoring ◽  
Cancer Treatment ◽  
Drug Monitoring ◽  
Kinase Inhibitors ◽  
Breast Cancer Treatment ◽  
Protein Kinase Inhibitors ◽  
Therapeutic Drug ◽  
Exposure Response

Protein kinase inhibitors (PKIs) represent up-to-date therapeutic approach in breast cancer treatment. Although cancer is a rapidly progressive disease, many substances, including PKIs, are usually used at fixed doses without regard to each patient’s individuality. Therapeutic drug monitoring (TDM) is a tool that allows individualization of therapy based on drug plasma levels. For TDM conduct, exposure-response relationships of drug substances are required. The pharmacokinetic data and exposure-response evidence supporting the use of TDM for 6 PKIs used in breast cancer treatment, one of the most common female tumour diseases, are discussed in this review.

scholarly journals Drug Sensitivity Screening and Targeted Pathway Analysis Reveal a Multi-Driver Proliferative Mechanism and Suggest a Strategy of Combination Targeted Therapy for Colorectal Cancer Cells

Molecules ◽  
2019 ◽  
Vol 24 (3) ◽  
pp. 623 ◽  
Author(s):  
Jinyan Shen ◽  
Li Li ◽  
Tao Yang ◽  
Niuliang Cheng ◽  
Gongqin Sun
Keyword(s):  
Colorectal Cancer ◽  
Targeted Therapy ◽  
Cell Lines ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Oncogenic Signaling ◽  
Colorectal Cancer Cells ◽  
Colorectal Cancer Cell Lines ◽  
Map Kinase Pathway ◽  
Oncogenic Signaling Pathways

Treatment of colorectal cancer mostly relies on traditional therapeutic approaches, such as surgery and chemotherapy. Limited options of targeted therapy for colorectal cancer narrowly focus on blocking cancer-generic targets VEGFR and EGFR. Identifying the oncogenic drivers, understanding their contribution to proliferation, and finding inhibitors to block such drivers are the keys to developing targeted therapy for colorectal cancer. In this study, ten colorectal cancer cell lines were screened against a panel of protein kinase inhibitors blocking key oncogenic signaling pathways. The results show that four of the 10 cell lines did not respond to any kinase inhibitors significantly, the other six were mildly inhibited by AZD-6244, BMS-754807, and/or dasatinib. Mechanistic analyses demonstrate that these inhibitors independently block the MAP kinase pathway, IR/IGF-1R/AKT pathway, and Src kinases, suggesting a multi-driver nature of proliferative signaling in these cells. Most of these cell lines were potently and synergistically inhibited by pair-wise combinations of these drugs. Furthermore, seven of the 10 cell lines were inhibited by the triple combination of AZD-6244/BMS-754807/dasatinib with IC50’s between 10 and 84 nM. These results suggest that combination targeted therapy may be an effective strategy against colorectal cancer.

scholarly journals Cyclin-Dependent Kinase Inhibitors and Their Therapeutic Potential in Colorectal Cancer Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Oana-Maria Thoma ◽  
Markus F. Neurath ◽  
Maximilan J. Waldner
Keyword(s):  
Colorectal Cancer ◽  
Cancer Treatment ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Direct Interaction ◽  
Special Focus ◽  
Cell Renewal ◽  
Cdk Inhibitors ◽  
Aberrant Expression ◽  
Cycle Regulation

Cyclin-dependent kinases (CDKs) are key players in cell cycle regulation. So far, more than ten CDKs have been described. Their direct interaction with cyclins allow progression through G1 phase, transitions to S and G2 phase and finally through mitosis (M). While CDK activation is important in cell renewal, its aberrant expression can lead to the development of malignant tumor cells. Dysregulations in CDK pathways are often encountered in various types of cancer, including all gastrointestinal (GI) tract tumors. This prompted the development of CDK inhibitors as novel therapies for cancer. Currently, CDK inhibitors such as CDK4/6 inhibitors are used in pre-clinical studies for cancer treatment. In this review, we will focus on the therapeutic role of various CDK inhibitors in colorectal cancer, with a special focus on the CDK4/6 inhibitors.

scholarly journals Inhibition of Development of Myxococcus xanthus by Eukaryotic Protein Kinase Inhibitors

1998 ◽  
Vol 180 (24) ◽  
pp. 6544-6550 ◽  
Author(s):  
Ritu Jain ◽  
Sumiko Inouye
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Myxococcus Xanthus ◽  
Large Family ◽  
Protein Kinase Inhibitors ◽  
Specific Gene ◽  
Fruiting Bodies ◽  
Fruiting Body Formation ◽  
Eukaryotic Protein Kinase ◽  
Eukaryotic Protein

ABSTRACT Myxococcus xanthus is a social bacterium that lives in the soil and undergoes spectacular development to form multicellular fruiting bodies. It contains a large family of eukaryote-like serine/threonine protein kinases. We found that a number of inhibitors for eukaryotic protein serine, threonine, and tyrosine kinases could inhibit the development and sporulation of M. xanthus to various degrees. These results suggest that serine/threonine and tyrosine phosphorylation may be involved in development of M. xanthus. None of the inhibitors tested had any effect on vegetative growth of M. xanthus. Most of them seemed to act during the early stages of development. However, the expression of a very early development-specific gene, Ω4521, was not significantly affected by the inhibitors. The patterns of protein phosphorylation during development were also not significantly altered by the inhibitors, suggesting that the targets of the inhibitors are minor or unstable phosphoproteins but play key roles in fruiting-body formation in M. xanthus.

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