Systematic molecular profiling of inhibitor response to the clinical missense mutations of ErbB family kinases in human gastric cancer

In this study, systematic inhibitor response to ErbB missense mutations in gastric cancer (GC) is investigated by combining computational analysis and experimental assay. The response profile is created for 6 ATP-competitive, reversible inhibitors against 9, 17, 5 and 17 GC-associated missense mutations of ErbB1, ErbB2, ErbB3 and ErbB4 kinase domains, respectively. From the profile a number of potential resistant and sensitive responses are identified theoretically. It is suggested that most ErbB mutations have only a modest effect on inhibitor binding, but few that are located around the kinase active site can influence the binding significantly. Structural examination reveals that steric hindrance and allosteric effect are primarily responsible for inhibitor resistance and sensitivity, respectively. Two ErbB2 mutations, namely V777L and T862A, are predicted to cause effective resistance on inhibitors TAK285 and Lapatinib, respectively. Kinase assays consistently observe that the mutations can reduce inhibitor activity by 4.9-fold and 2.4-fold, with IC50 changing from 29 to 16 nM (wild type) to 83 and 39 nM (mutant) for TAK285 and Lapatinib, respectively.Graphical abstract
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research

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CONCLUSION: Our data show that fluorouracil-based adjuvant chemotherapy does not work for dMMR cases, if not worse. Autophagy inhibition and/or immune checkpoint inhibition might be promising alternative strategies for gastric cancer treatment. IMPLICATIONS FOR PRACTICE: The use of microsatellite instability (MSI) and mismatch repair (MMR) as predictive biomarkers for adjuvant chemotherapy in colorectal cancer has caused a paradigm shift in cancer therapy, although its implications in gastric cancer are still questionable. The data obtained in the current study indicate that MSI-MMR is an independent prognostic factor...
Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Oncologist Source Type: research
This study provides strong evidence that following a healthy lifestyle can substantially extend the years a person lives disease-free." Commentary on Recent Evidence for Cognitive Decline to Precede Amyloid Aggregation in Alzheimer's Disease https://www.fightaging.org/archives/2020/01/commentary-on-recent-evidence-for-cognitive-decline-to-precede-amyloid-aggregation-in-alzheimers-disease/ I can't say that I think the data presented in the research noted here merits quite the degree of the attention that it has been given in the popular science press. It is interesting, but not compelling if its role...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Authors: Li D, Cui R, Xu S, Liu Y Abstract Combined administration of different drugs is a widely acknowledged approach for effective cancer therapy. However, the limited targeting, as well as inferior drug loading capacities of current drug delivery systems (DDS), are still the bottleneck for better performance in cancer treatment. Herein, we successfully developed a cancer cell membrane (CM) decorated calcium carbonate (CC) hybrid nanoparticles (HN) for the co-delivery of cisplatin (CDDP) and oleanolic acid (OA). The physicochemical property of HN/CDDP/OA was evaluated, which revealed that the as-prepared DDS was...
Source: Drug Delivery - Category: Drugs & Pharmacology Tags: Drug Deliv Source Type: research
Conclusions/implicationsPPI use may impair breast cancer survivors ’ memory, concentration, and quality of life.
Source: Journal of Cancer Survivorship - Category: Cancer & Oncology Source Type: research
The U.S. Food and Drug Administration approved Blueprint Medicines Corp's oral therapy to treat a rare form of cancer that affects the stomach and small intestine, the agency said on Thursday.
Source: Reuters: Health - Category: Consumer Health News Tags: healthNews Source Type: news
Publication date: Available online 16 December 2019Source: Acta Pharmaceutica Sinica BAuthor(s): Zhenzhen Liu, Taoqian Zhao, Zhonghua Li, Kai Sun, Yundong Fu, Ting Cheng, Jimin Guo, Bin Yu, Xiaojing Shi, Hongmin LiuAbstractUbiquitin specific peptidase 28 (USP28) is closely associated to the occurrence and development of various malignancies, and thus has been validated as a promising therapeutic target for cancer therapy. To date, only few USP28 inhibitors with moderate inhibitory activity have been reported, highly potent and selective USP28 inhibitors with new chemotypes remain to be discovered for pathologically investi...
Source: Acta Pharmaceutica Sinica B - Category: Cancer & Oncology Source Type: research
We reported a case of advanced gastroesophageal junction cancer with distal lymph node metastasis that was successfully treated with chemotherapy, surgical resection, and nivolumab therapy. An aggressive search for biomarkers implying benefit effects of nivolumab should be performed.
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Authors: Liu H, Mei D, Xu P, Wang H, Wang Y Abstract Yes-associated protein (YAP) has been reported to serve an important role in gastric cancer cell survival and migration. However, the underlying mechanism remains unclear. The aim of present study was to identify the underlying mechanism through which Yap sustains gastric cancer viability and migration. The results of the present study demonstrated that YAP expression was upregulated in gastric cancer MKN-28/74 cells compared with normal gastric GES-1 cells. Functional studies revealed that silencing of YAP inhibited gastric cancer MKN-28/74 cell viability and in...
Source: Oncology Letters - Category: Cancer & Oncology Tags: Oncol Lett Source Type: research
In this report, 7-ethyl-10-hydroxycamptothecin (SN-38) coated graphene oxide synthesized (SN-rGO) effectively and are characterized using various analytical methods. The hydroxyl and carbonyl gatherings of oxidized SN38 will in general ingest onto GO by means of hydrogen bond arrangement with their leftover oxygen functionalities and offers steadiness to SN38. The morphological analyses showed the foldable fields of SN38-rGO NPs with acquire transparency, thin sheets and the crumpled structures. Further the photothermal efficiency and cytotoxicity of the SN-rGO were examined by MTT assay using two NCI-N87 and SGC-791 gastr...
Source: Journal of Photochemistry and Photobiology B: Biology - Category: Speech-Language Pathology Source Type: research
CONCLUSION: Although, in this study, duloxetine had less genotoxicity than cisplatin in concentrations under 200 μ M and showed cytotoxic effects as well, due to its IC50, it cannot be considered as a better choice for gastric cancer therapies with respect to cisplatin as a common anticancer drug.RESUMO CONTEXTO: O c âncer gástrico é a segunda principal causa de morte relacionada ao câncer globalmente. Infelizmente, a taxa de sobrevivência dos pacientes com câncer gástrico que se submeteram à quimioterapia após a cirurgia, tem sido inferior à metade. Al&e...
Source: Arquivos de Gastroenterologia - Category: Gastroenterology Source Type: research
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