Now, with the successful translation of selective BRAF and MEK inhibitors into validated therapies for BRAF mutant melanoma, the field seeks to resolve the role for these agents in cancers harbouring RAS mutations or those driven by aberrant growth factor receptor activation.
Interesting, Prof. Peng Hou and colleagues, at the First Affiliated Hospital of Xi'an Jiaotong University in China, identified unknown epigenetic mechanisms and their involvement in the tumorigenesis of B-RAF(V600E)-driven cancer.
Using patient-derived (V600E)BRAF melanoma cells, we found that low-glutamine-induced histone hypermethylation resulted in cancer cell dedifferentiation and resistance to BRAF inhibitor treatment, which was largely mediated by methylation on H3K27, as knockdown of the H3K27-specific demethylase KDM6B and the methyltransferase EZH2 respectively reproduced and attenuated the low-glutamine effects in vitro and in vivo.
Associations between BRAFV600E and TERT promoter mutations and clinicopathological features, Tumor-Node-Metastasis stage, initial risk, response to therapy, follow-up, and final disease outcome were assessed according to American Thyroid Association 2015 criteria and the American Joint Committee on Cancer/Tumor-Node-Metastasis (8th edition) staging system.Median follow-up was 120 months.
Secondary cutaneous malignancies are a well-documented toxicity of vemurafenib, thought to be mediated by enhanced ERK signalling in BRAF wild-type, RAS-mutant cells.
In sum, we were able to screen up to nine cancer samples on a single BRAF microarray (three per CDH on three regions per slide), indicating that this method may dramatically decrease the experimental time, cost, and effort of mutation detection in BRAF and other genes amenable to microarray analysis.
Recently, increasing evidences indicate that BRAF((V600E)) mutation is a specific molecular feature and driver of the serrated pathway, and proximal serrated polyps with BRAF((V600E)) mutation have a high risk of progression to malignancy.
RAS mutation has limited value in predicting malignancy among BRAF mutation-negative thyroid nodules with AUS/FLUS cytology and further, investigation is anticipated to evaluate the true role of RAS mutation in thyroid malignancy.
Among these kinases, the RAF and MEK kinases have received substantial attention, owing largely to the relatively high frequency of activating mutations of RAS ( approximately 20% of all human cancers), an upstream activator of the well established RAF-MEK-ERK signaling cascade, as well as frequent activating mutations in the BRAF kinase ( approximately 7% of all human cancers).
However, only the detection of BRAF mutations predicts the presence of (papillary) thyroid malignancy with almost 98% probability, indicating necessity of oncologic thyroid resections irrespective of the cytology result.
Also highlighted are the functional consequences of aberrant splice variants (<i>BCR-Abl35INS</i>, <i>BIM-γ</i>, <i>IK6</i>, <i>p61 BRAF V600E</i>, <i>CD19-∆2</i>, <i>AR-V7</i> and <i>PIK3CD-S</i>) in promoting resistance to cancer targeted therapy or immunotherapy.
The AUS-NA subcategory was associated with the highest risk of malignancy and the greatest frequency of BRAFV600E (substitution of valine to glutamic acid at position 600) mutation.
Activating point mutations of the serine/threonine kinase gene BRAF located on 7q34 are found in a wide range of malignancies, with the highest frequency (66%) occurring in malignant melanomas.
These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general.
Methods In this phase II, open-label trial, patients with predefined BRAFV600E-mutated malignancies received dabrafenib 150 mg twice daily and trametinib 2 mg once daily until unacceptable toxicity, disease progression, or death.