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Biomarkers for the Management of Malignancies with BRAF Mutation
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Vemurafenib, dabrafenib, and encorafenib inhibit BRAFV600E/K [19, 20] and induce objective tumor responses. However, durability of response to BRAF inhibitor monotherapy treatment is limited by the emergence of drug resistance [21]. In addition, neither vemurafenib nor dabrafenib as a single agent was active in BRAF-mutant colorectal [22]. Furthermore, certain patients with mutant BRAF-driven tumors showed evidence of paradoxical activation of MAPK pathway upon BRAF inhibition [13]. These patients manifested signs of cutaneous neoplasms, including squamous cell carcinomas. In these patients, secondary mutations in HRAS were observed and attributed as a mechanism to potentiate BRAF inhibitor-induced paradoxical activation of the MAPK pathway to induce these secondary skin cancers.
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
An individual may have a genetic predisposition for a certain cancer. Defective genes can be inherited, increasing the risk of cancer in subsequent generations. There are numerous possible genetic faults that can lead to cancer. Proto-oncogenes are genes that normally code for proteins that are involved in the control of cell division and differentiation. If they become mutated into an oncogene, this may disrupt the normal function of the gene and without control mechanisms in place, the cell could become cancerous. For example, the Ras protein is involved in the signalling pathway leading to cells division, during the processes of mitosis and meiosis. In normal cells, this protein has the self-regulating ability to switch itself off. In the mutated gene, Ras loses this ability, and is continually active leading to uncontrolled cell division. This mutation is found to be present in around one-fifth of human cancers.
Costello Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The HRAS gene consists of six exons, five of which are involved in the production of a 189 aa, 21 kDa protein (HRAS). Most pathogenic HRAS variants result from missense substitutions that disrupt guanine nucleotide binding and reduce in intrinsic and GAP-induced GTPase activity of the HRAS protein, keeping HRAS in the active state, and increasing HRAS binding affinity and constitutive activation (gain-of-function or hyperactivation) of its downstream targets including RAF, PI-3, and RalGEF [11]. This contributes to phenotypic abnormalities associated with Costello syndrome (e.g., facial dysmorphism, mild to moderate intellectual disability, and increased anxiety) as well as predisposition to several tumors (e.g., cutaneous papilloma, rhabdomyosarcoma [60% of cases], transitional cell carcinoma, and neuroblastoma) [12,13]. In fact, the substitution of glycine to serine (G12S) at codon 12 in exon 1 accounts for 80% of clinical cases. Other notable HRAS mutations identified in Costello syndrome include p.Gly13Asp and p.Gly60Asp [14].
Novel approaches for the development of direct KRAS inhibitors: structural insights and drug design
Published in Expert Opinion on Drug Discovery, 2022
Kashif Haider, Anku Sharma, M Shahar Yar, Prasanna Anjaneyulu Yakkala, Syed Shafi, Ahmed Kamal
Hyperactivated RAS signaling is usually observed in many tumors. Among all RAS isoforms, mutation of KRAS oncogenes is frequently found in various types of solid tumors. A substantial proportion of KRAS mutations are found in patients with pancreatic ductal adenocarcinomas (PDAC; approx. 90%), metastatic colorectal cancers (CRC; approx. 30%-50%), and non-small cell lung cancers (NSCLC; approx. 15%-25%). Whereas, NRAS and HRAS mutations are frequently harbored in myeloid leukemia and bladder cancers [8,9]. Targeting functionality of RAS could be clinically beneficial to address the unmet medical need of the cancer patients. KRAS mutations mainly occur at codon G12, G13, and Q61 sites, which mostly depends on the type of cancer [10]. To counter such indications several small-molecule inhibitors are being investigated and currently are in the late phases of clinical trials. In Table 1, we have illustrated some of the inhibitors which are in the different phases of clinical development.
Fe3O4 Nanopowders: Genomic and Apoptotic Evaluations on A549 Lung Adenocarcinoma Cell Line
Published in Nutrition and Cancer, 2020
Ayse Kaplan, Hatice Mehtap Kutlu, Gulsen Akalin Ciftci
The down regulation of SRC gene has been shown as a new strategy in the treatment of solid tumors (53). In our work, this gene was downregulated by IC30 value of Fe3O4 nanopowders and we think that the downregulation of this gene induce apoptosis in A549 cells. The HRAS gene has been overexpression in various types of cancer (54,55). The CDC34 gene has been also overexpression in MM (multiple myeloma) cells (56). In addition, EIF4G1 gene has been over expressed in nasopharyngeal carcinoma cells (57). The EIF5A gene has been overexpressed in HCC (hepatocellular carcinoma), ovarian cancer and lung cancer (58). As a result, these genes have been shown as therapeutic markers. In our work, these genes were downregulated by IC30 value of Fe3O4 nanopowders and can be effective on apoptotic pathways. The EIF2C2, ANG and NUCKS1 genes were downregulated by IC50 value of cisplatin and IC30 value of Fe3O4 nanopowders in A549 cells. These findings show that Fe3O4 nanopowders may affect same apoptotic pathway such as cisplatin.
Update on BRAF and MEK inhibition for treatment of melanoma in metastatic, unresectable, and adjuvant settings
Published in Expert Opinion on Drug Safety, 2019
Kristy Kummerow Broman, Lesly A Dossett, James Sun, Zeynep Eroglu, Jonathan S Zager
In the phase I dose escalation trial, increases in the dose of vemurafenib beyond 960 mg twice daily were limited by grade 2 or 3 rash, fatigue and arthralgia [32]. Adverse events (AE) appeared proportional to drug dose and exposure. During the extension phase, 41% of patients (13/32) required dose reduction. Ten patients (31%) developed squamous cell carcinoma (SCC), keratoacanthoma type. These lesions were characterized by the rapid eruption of individual dome-shaped non-pigmented lesions, the majority of which (60%) harbored a RAS mutation (most common in HRAS) [38]. Increased proliferation of HRAS-mutant cell lines exposed to vemurafenib was associated with a paradoxical re-activation of MAPK signaling. A vemurafenib analog (PLX4720) accelerated the growth of the lesions harboring HRAS mutations, and this growth was inhibited by concomitant treatment with a MEK inhibitor.