AI Article Synopsis
- The study investigates how the dual BRAF inhibitor AZ304 affects colorectal cancers with different BRAF mutations.
- AZ304 was found to inhibit both wild type and V600E mutant BRAF types effectively, showing strong anti-tumor effects in vitro and in vivo.
- The combination of AZ304 with the EGFR inhibitor Cetuximab further enhances its therapeutic efficacy against colorectal cancers, regardless of their BRAF mutation status.
Article Abstract
Background: BRAF mutation is associated with poor clinical outcome of patients with malignant tumours, and mediates resistance to chemotherapy and targeted therapy. This study aimed to determine whether V600E mutant and wild type BRAF colorectal cancers exhibit distinct sensitivities to the dual BRAF inhibitor AZ304.
Methods: Kinase activity was assessed by the AlphaScreen assay. Then, MTT assay, EdU assay, colony-formation assay and Western blot were performed to evaluate the anti-tumour effects of AZ304 in vitro. In vivo efficacy was investigated by xenograft analysis and immunohistochemistry.
Results: AZ304 exerted potent inhibitory effects on both wild type and V600E mutant forms of the serine/threonine-protein kinase BRAF, with IC values of 79 nM and 38 nM, respectively. By suppressing ERK phosphorylation, AZ304 effectively inhibited a panel of human cancer cell lines with different BRAF and RAS genetic statuses. In selected colorectal cancer cell lines, AZ304 significantly inhibited cell growth in vitro and in vivo, regardless of BRAF genetic status. In addition, the EGFR inhibitor Cetuximab enhanced the potency of AZ304 independently of BRAF mutational status.
Conclusions: The BRAF inhibitor AZ304 has broad spectrum antitumour activity, which is significantly enhanced by combination with Cetuximab in colorectal cancers in vitro and in vivo.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988692 | PMC |
| http://dx.doi.org/10.1038/s41416-018-0086-x | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Optimizing Treatment of V600E-Mutant Metastatic NSCLC With Encorafenib and Binimetinib: A Practical Resource for Advanced Practice Providers.
J Adv Pract Oncol
September 2024
Memorial Sloan Kettering Cancer Center, New York, New York.
The V600E mutation aberrantly activates the mitogen-activated protein kinase (MAPK) pathway, subsequently resulting in uncontrolled cellular proliferation, survival, and dedifferentiation. Approximately 2% of patients with non-small cell lung cancer (NSCLC) have a V600E mutation. BRAF and MEK inhibitor combination therapy targets two kinases within the MAPK pathway.
View Article and Find Full Text PDFHDAC and MEK inhibition synergistically suppresses HOXC6 and enhances PD-1 blockade efficacy in BRAF-mutant microsatellite stable colorectal cancer.
J Immunother Cancer
January 2025
Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery III, Peking University Cancer Hospital & Institute, Beijing, China
Background: B-Raf proto-oncogene, serine/threonine kinase (BRAF)-mutant microsatellite stable (MSS) colorectal cancer (CRC) constitutes a distinct CRC subgroup, traditionally perceived as minimally responsive to standard therapies. Recent clinical attempts, such as BRAF inhibitors (BRAFi) monotherapy and combining BRAFi with other inhibitors, have yielded unsatisfactory efficacy. This study aims to identify a novel therapeutic strategy for this challenging subgroup.
View Article and Find Full Text PDFImpact of BRAF and MEK Inhibitors on Gingival Hyperplasia in Melanoma Patients-A Case Report.
J Clin Med
December 2024
Department of Dental Medicine, Faculty of Medicine, University of Novi Sad, 21000 Novi Sad, Serbia.
: Although BRAF inhibitors, such as vemurafenib, produce a marked response in patients with advanced melanoma with a BRAF V600 mutation, they eventually develop resistance to this treatment. To address this issue, vemurafenib is increasingly combined with the MEK inhibitor cobimetinib, leading to improved response rates and enhanced survival. However, this treatment modality is associated with numerous side effects.
View Article and Find Full Text PDFDynamic Changes in Circulating Tumor DNA During Immunotherapy for Head and Neck Cancer: SHIZUKU-HN Study.
Int J Mol Sci
December 2024
Department of Medical Oncology, Institute of Science Tokyo, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8510, Japan.
Immune checkpoint inhibitors (ICIs) are effective in treating recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but only 20% of patients achieve durable responses. This study evaluated circulating tumor DNA (ctDNA) as a real-time biomarker for monitoring treatment response in HNSCC. The SHIZUKU-HN study prospectively collected and analyzed serial plasma samples (n = 27) from HNSCC patients undergoing ICIs, using Guardant360 to assess ctDNA variant allele frequency (VAF) and genetic mutations.
View Article and Find Full Text PDFA Childhood Langerhans Cell Histiocytosis With a Novel BRAFN486_T491delinsK Mutation: Good Response to Conventional Chemotherapy.
J Pediatr Hematol Oncol
January 2025
Department of Pediatrics, West China Second University Hospital, Sichuan University, Sichuan, China.
Langerhans cell histiocytosis (LCH) is characterized genetically by diverse gene mutations of the mitogen-activated protein kinase signaling cascade. BRAFN486_T491delinsK mutation is a rare mutation that involves the β2-αC ring domain, causing activation of the mitogen-activated protein kinase pathway, and is predicted to be resistant to the chemotherapy and BRAFV600E inhibitor in adult LCH cases. Here, we report a childhood LCH case with this novel BRAF mutation and had a good response to conventional chemotherapy.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!