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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Both normal and mutated Ras proteins need to anchor to the cell membrane for signal transduction to occur (Figure 6.54). Attachment to the membrane occurs through several post-translational modifications, in particular the transfer of a 15-carbon isoprenoid group to the carboxy-terminal of the Ras protein, a process known as prenylation. This isoprenoid group ensures that Ras can attach to its correct intracellular membrane-bound location. Thus, the membrane-bound Ras protein represents a “molecular switch” that allows transport of a signal (e.g., a growth factor) from the external environment of a cell to its nucleus. The first stage of this process involves an extracellular ligand stimulating a monomeric receptor kinase (RTK) that then dimerizes. Next, Grb2, an initial adaptor protein, identifies and interacts with a binding site, which in turn allows recruitment of “Son of Sevenless” (SoS), a second adaptor protein. The latter causes the inactive GDP-carrying Ras to become active by substituting GDP for GTP. After this, the signal can be transmitted downstream by the activated Ras to other effectors, such as Raf. In the MAPK signaling pathway, the Raf protein is the first kinase in the signaling chain.
Biomarkers for the Management of Malignancies with BRAF Mutation
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Class 1 and Class 2 tumors respond to BRAF inhibitor-targeted therapy. Class 1 BRAF V600D/E/K/R mutations function as hyperactive monomers in a RAS dispensable manner and result in strong activation of BRAF kinase activity, and constitutive activation of MAPK pathway. These mutations are sensitive to BRAF and MEK inhibitors [16, 17]. Class 2 mutants are located in the activation segment or P-loop of the BRAF protein and signal as RAS-independent dimers. Examples of Class 2 mutants are BRAF G464V/E, G469A/V/R, and BRAF translocations resulting in fusion proteins. Fusion proteins are created following translocation of BRAF kinase domain with N-terminal partner genes such as SRY-Box 10 (SOX10), acylglycerol kinase (AGK), and septin3 (SEPT3) altering BRAF function, copy number, and activity. Oncogenic BRAF gene fusions that activate BRAF have been found in melanomas and other cancers [16, 18]. Class 3 mutants are located in the P-loop, catalytic loop, or DFG motif and have basal kinase activity that is lower than wild-type BRAF or lack kinase activity. Examples of Class III mutants are BRAF D287H, V459L, and G466A/E/V. Biological and clinical significance and therapeutic responsiveness of RAF variants is an area of current investigation.
Post-Treatment Surveillance of Thyroid Cancer
Published in Madan Laxman Kapre, Thyroid Surgery, 2020
The most common mutation studied for prognostic implication in thyroid cancer is B-RAF. B-RAFV600E is the most common driver mutation, being present in 40%–60% of all PTCs, especially in classical and tall cell variants [33]. In several series, this mutation was associated with adverse pathological factors like multifocality, ETE, lymph nodal metastases, distant metastases, and increased risk of recurrence and mortality [32]. However, the impact of B-RAF positivity in some studies was not independent of other tumor features, thus making the interpretation difficult. Furthermore, the clinical application of B-RAFV600E as a prognostic marker is marred by its low specificity [32]. Thus, B-RAF is unlikely to be used in isolation, but only in conjunction with other prognostic variables in a multivariable context [34]. Though B-RAF features in the ATA risk stratification model (see Table 20.1) for its incremental prognostic value, the ATA does not routinely recommend B-RAF evaluation for initial post-operative risk stratification [7].
Tumor-infiltrating lymphocytes for melanoma immunotherapy
Published in OncoImmunology, 2023
Oliver Kepp, Peng Liu, Laurence Zitvogel, Guido Kroemer
An activating mutation in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene (BRAFV600E) is present in more than 50% of melanoma patients. Thus, combination of dabrafenib plus trametinib is yet another treatment option for melanoma harboring such mutation. Although this therapy is associated with a high initial response rate, most patients develop resistance over time.2 Further combination approaches involving BRAF inhibition plus immune checkpoint blockade as well as the use of novel immune checkpoint blocking antibodies targeting lymphocyte-activation gene 3 (LAG-3) LAG3 have shown promising response rates. Thus, combination of anti-PD-1 and anti-LAG3 monoclonal antibodies has been associated with objective responses in 16% of patients with refractory disease but follow-up data are still missing.5 Nevertheless, as it stands the efficacy of both immune checkpoint inhibition or targeted approaches for patients with advanced stage melanoma remains limited and despite optimal treatment about half of the patients will eventually die from the disease.
B-Raf inhibitor vemurafenib counteracts sulfur mustard-induced epidermal impairment through MAPK/ERK signaling
Published in Drug and Chemical Toxicology, 2023
Zhiyong Xiao, Feng Liu, Junping Cheng, Ying Wang, Wenxia Zhou, Yongxiang Zhang
The Raf family of kinases (A-Raf, B-Raf, and C-Raf) are serine/threonine kinases that catalyze the phosphorylation and activation of MEK1 and MEK2, which in turn phosphorylate and activate extracellular signal-regulated kinases 1 and 2 (ERK1/2). Raf kinases have been extensively studied since they were first identified in the early 1980s as retroviral oncogenes, particularly when active mutations of B-Raf were reported in a large number of tumors (Davies et al.2002). Vemurafenib is the first specific kinase inhibitor approved for the treatment of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib (Roskoski 2018). Interestingly, previous studies have revealed that SM induces the activation of epidermal growth factor receptor (EGFR) on the cell surface and then activates the downstream Ras-Raf-MEK-ERK pathway (Mukhopadhyay et al.2008, 2009, Rebholz et al.2008, Popp et al.2011, Karacsonyi et al.2012).
Deciphering the genotype and phenotype of hairy cell leukemia: clues for diagnosis and treatment
Published in Expert Review of Clinical Immunology, 2019
Margot C.E. Polderdijk, Michiel Heron, Saskia Kuipers, Ger T. Rijkers
Theoretically, any of the 766 codons coding for the B-Raf protein could be the site of a mutation, leading to a change in amino acid sequence. This does not automatically lead to a change in secondary, tertiary or quaternary protein structure, so in fact, most of these mutations will not lead to impaired function. Those mutations that do cause changes are the ones recurrently found in tumors. The most common of these is the V600E (or at the nucleotide level: T1799A) mutation, which accounts for about 80–90% of activation segment mutations [50,51]. In this mutation, thymine is exchanged for adenosine (GTG → GAG), so that valine (V) is exchanged for glutamic acid (E). Wan et al. [52] described how this mutation constitutively activates the RAF-ERK pathway. B-Raf proteins (mutated or wild type) either homodimerize or form a complex with a C-Raf protein, and these dimers then can activate ERK. The substitution of glutamic acid for valine affects the kinase domain, making it about 500 times more active than in wild type BRAF. Thevakumaran et al. [53] have used crystal structures to show that the larger glutamic acid residue forces the activation segment into the active position, making the physiological activation by phosphorylation unnecessary. Other mutations, accounting for 10–20% of BRAF mutations in cancer, are difficult to summarize, because of their large variation.