Our findings unveil the potential of laminB1 as both a diagnosis marker and a therapeutic target of melanoma.

P1, N=28, Recruiting, Fore Biotherapeutics | N=12 --> 28

Molecular docking experiments are thoroughly examined to validate the binding interactions of the most active hybrids with the active sites of EGFR and BRAFV600E. The data indicated that the examined compounds can efficiently engage with essential amino acid residues in both kinases.

P2, N=21, Recruiting, City of Hope Medical Center | Initiation date: Nov 2024 --> Jul 2024

P1, N=15, Terminated, ABM Therapeutics Shanghai Company Limited | N=52 --> 15 | Trial completion date: May 2028 --> Aug 2024 | Recruiting --> Terminated | Trial primary completion date: May 2028 --> Aug 2024; Adjustment of the applicant's research and development strategy

P1, N=20, Terminated, ABM Therapeutics Shanghai Company Limited | N=72 --> 20 | Trial completion date: Aug 2025 --> Jun 2024 | Recruiting --> Terminated | Trial primary completion date: Aug 2025 --> Jun 2024; Adjustment of the applicant's research and development strategy

P=N/A, N=12, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: May 2025 --> Nov 2024 | Trial primary completion date: May 2025 --> Nov 2024

Targeted therapies against RAF kinases have achieved substantial success, especially in BRAF-V600E-mutant melanomas, where inhibitors like vemurafenib and dabrafenib have demonstrated remarkable efficacy, leading to improved patient outcomes. This review discusses the clinical advancements in RAF-targeted therapies, with a focus on ongoing efforts to overcome therapeutic resistance and enhance outcomes for cancer patients. It also underscores the persistent challenges in effectively targeting RAF kinase in oncology.

FOXN3 functions as an important regulator of the development and progression of Vemurafenib-resistant melanoma cells, partly owing to its binding to the FISP1. As such, FOXN3 may represent a relevant target for therapeutic interventions in patients suffering from drug-resistant melanoma.

Vemurafenib cannot be considered cost-effective in terms of what has normally been considered a reasonable willingness to pay (WTP) in Tunisia. A significant price reduction would be necessary to bring the incremental cost-effectiveness ratio to an acceptable level.

P2, N=4, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025

Compound 9c showed the highest activity with IC50 = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC50 = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B-RAFWT and mutated B-RAFV600E with IC50 = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC50 = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively...Compound 9c increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B-RAF active site.

Hairy cell leukemia is an uncommon B-cell malignancy with excellent response to purine analogs and to targeted therapies such as ibrutinib and vemurafenib. Only one patient in our cohort passed away due to infection. Estimated 10-year overall survival was 99% suggesting that infections may not cause as much mortality as was seen prior to current therapies.

Two frontline BRAF inhibitors (BRAFi), vemurafenib and dabrafenib, are frequently used to treat unresectable or metastatic BRAF V600E melanoma. Our data support the feasibility of the development of CRISPR-Cas therapeutic approaches to the treatment of melanoma. Successful therapeutic CRISPR-directed gene editing would enable both specific and efficient editing of a mutation-specific targeting approach eliminate concern for on- and off-target damage to the genomes of healthy cells.

Due to the relevance of the BRAFV600E mutation, inhibitors to this kinase have been developed, vemurafenib-OMe and dabrafenib. Ligand-protein interactions were evaluated using Schrödinger-Maestro program, LigPlot + , and PLIP (protein-ligand interaction profiler). Finally, all of the protein figures presented in this article were made in the PyMOL program.

BRAF alterations, specifically BRAF mutations and BRAF fusions, facilitate resistance to EGFR-TKIs. Triple-targeted therapy is effective and safe for patients with EGFR-mutant NSCLC with acquired BRAF alterations, mainly among patients with BRAF class I mutations and potentially in patients with BRAF fusions.

Cell proliferation of the cells after the treatment with LE-127/2, parent CBG or vemurafenib was assessed by Cell Titer Blue Assay...LE-127/2 also induced the expression of some proteins involved in apoptosis, and it is particularly noteworthy the increased level of cleaved PARP. Based on the results obtained, it can be concluded that LE-127/2 induced autophagy could lead to the inhibition of cell proliferation and death in melanoma cells.

P3, N=514, Completed, Hoffmann-La Roche | Active, not recruiting --> Completed

Although a rare occurrence and known to have a poor prognosis, B-Raf mutation positive programmed death ligand 1 overexpressed lung adenocarcinoma presenting with metastatic musculoskeletal lesions can respond favorably to a combination immune checkpoint inhibitor and BRAF inhibitor medication.

We leveraged a fluorescent biosensor to confirm that B-RAF inhibitors, dabrafenib and vemurafenib, paradoxically activated ERK in human keratinocytes and organotypic epidermis, disrupting cell-cell junctions and weakening epithelial integrity. Validating these results, we demonstrated ERK hyperactivation in patient biopsies from vemurafenib-induced Grover disease, but also from spontaneous Grover disease, revealing a common etiology for both. Finally, in line with our recent identification of ERK hyperactivation in Darier disease, a genetic disorder with identical pathology to Grover disease, our studies uncovered that the pathogenic mechanisms of these two diseases converge on ERK signaling and support MEK inhibition as a therapeutic strategy. .

The present study demonstrates a notably high V600E frequency (12.2%) in comparison to global reported data, which ranges from 0.4 to 18%. This finding reflects the importance of upfront BRAF testing of the genetically distinct population of Pakistan. Previously unreported mutations identified in the sample may be of clinical significance and warrant further investigation. The concomitant high expression and significant association between CD133 and BRAFV600E represent vital actionable genes that may be targeted together to improve CRC patient management.

P1, N=15, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The tetracaine treatment could reduce drug resistance via neddylation signaling pathway inactivation in melanoma cells. These findings demonstrate that tetracaine effectively inhibits cell proliferation and alleviates vemurafenib resistance in melanoma by suppressing the neddylation signaling pathway, providing a promising avenue for controlling cancer progression.

Vemurafenib resistance can lead to an increase in EGF and EGFR levels, causing activation of the EGFR signaling pathway, which promotes YAP1 nuclear localization to increase the expression of STIM1. Our findings not only reveal the mechanism by which vemurafenib resistance promotes STIM1 upregulation, but also provide a rationale for combined targeting of the EGF/EGFR-YAP1/TEAD2-STIM1 axis to improve the therapeutic efficacy of BRAF inhibitor in melanoma patients.

P2, N=250, Recruiting, Fore Biotherapeutics | N=135 --> 250

P2, N=12, Active, not recruiting, HonorHealth Research Institute | Recruiting --> Active, not recruiting | Trial primary completion date: Jun 2024 --> Oct 2024

P2, N=86, Recruiting, Memorial Sloan Kettering Cancer Center | Not yet recruiting --> Recruiting

Patients suffering from BRAF mutant melanoma have tumor recurrence within merely 7 months of treatment with a potent BRAF inhibitor (BRAFi) like vemurafenib...Since PTEN plasmid and ARV are distinct in their physicochemical properties, we fabricated PTEN-plasmid loaded lipid nanoparticles (PL-NANO) and ARV-825-loaded nanoliposomes (AL-NANO) to yield a mean particle size of less than 100 nm and greater than 99% encapsulation efficiency for each therapeutic payload...Importantly, simultaneous delivery of PL-NANO and AL-NANO achieved significant upregulation of PTEN expression levels and degradation of BRD4 protein to ultimately downregulate c-Myc levels in BRAFi-resistant melanoma cells. Altogether, lipid nanocarriers delivering this novel lethal cocktail stands as one-of-a-kind gene therapy to target undruggable c-Myc oncogene in BRAFi-resistant melanoma.

Mouse and human BRAFV600E melanomas with or without ARID1A expression were transformed into resistant to vemurafenib, an FDA-approved specific BRAFV600E inhibitor...Furthermore, the neoantigens that emerge with therapy resistance can be promising therapeutic targets for refractory tumors. Significance: Chemotherapy resistance promotes the acquisition of immunogenic neoantigens in ARID1A-deficient tumors that confer sensitivity to immune checkpoint blockade and can be utilized for developing antitumor vaccines, providing strategies to improve immunotherapy efficacy.

Our results show that BRAFm dMMR/MSI-H mCRC patients benefit from BRAFi+EGFRi+/-MEKi after progression under ICIs. Despite lower ORR and DCR, the outcome is not different from that observed in pMMR/MSS BRAFm CRC and is in line with the results of the BEACON registration trial.

These cases represent the first reported instances of off-label vemurafenib use in Brazil for the treatment of LCH and both patients have demonstrated excellent responses to the medication. However, the long-term side effects are unknown in children, and prospective studies are needed. In addition, there is a lack of epidemiological data on histiocytosis in Brazil and studies evaluating the budgetary impact of incorporating BRAF mutation research and the use of vemurafenib into the public health system. These reports could be a starting point.

Tretinoin also enhanced the antitumor effect of a combination of the BRAF inhibitor and anti-EGFR antibody with or without MEK inhibitor in a BRAFV600E CRC xenograft mouse model. Our data provide a rationale for developing retinoids as a new combination agent to overcome resistance to the combination therapy for patients with BRAFV600E CRC.

In summary, this work describes BRAF/MEK-inhibitor-resistant melanoma cells, allowing for better understanding the underlying mechanisms of resistance. The results may thus contribute to the development of new, more effective therapeutic strategies.

P2, N=36, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Oct 2025 --> Aug 2024 | Trial primary completion date: Oct 2025 --> Aug 2024

P2, N=86, Not yet recruiting, Memorial Sloan Kettering Cancer Center

These studies identify miR-876 as a distinct tumor suppressor on 9p21 that is inactivated in melanoma and suggest miR-876 loss as an additional mechanism to activate ERK and the mitogen activated protein kinase (MAPK) pathway in melanoma. In addition, they suggest the therapeutic potential of combining miR-876 overexpression with BRAF inhibition as a rational therapeutic strategy for melanoma.

Due to the up-regulation of PD-1/PD-L1 receptors in tumors treated with BRAF/MEK inhibitor therapy, further studies included a third combination agent, anti-PD-1/PD-L1 inhibitors. This triple combination therapy may have superior efficacy and a manageable safety profile when compared with single or double agent therapy regimens.

P1, N=316, Recruiting, Haisco Pharmaceutical Group Co., Ltd.

In this study, the role of integrins and TGF-β signalling in vemurafenib resistance in melanoma was investigated, and the potential of combining vemurafenib with cilengitide as a therapeutic strategy was investigated. Additionally, this combination therapy significantly decreased invasion and colony formation in these resistant cells. In conclusion, it is suggested that targeting integrins and TGF-β signalling, specifically ITGA5, ITGB3, PAI1, and p21, may offer promising approaches to overcoming vemurafenib resistance, thereby improving outcomes for metastatic melanoma patients.

P1/2, N=113, Completed, Fore Biotherapeutics | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Jul 2024

P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRAF inhibitor (vemurafenib) efficacy in BRAFV600E-mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.

"VEM+COB is active in a range of advanced solid tumours and 1L NSCLC with a BRAF V600 mutation."