Zelboraf (vemurafenib)

Cutaneous melanoma cell lines (A375 and SK-MEL-28) were transfected by CENPM siRNA (si-CENPM), followed by detections and treatment of various concentrations of dabrafenib and vemurafenib. Clinically, GEPIA database revealed that CENPM was upregulated and correlated with worse overall survival in cutaneous melanoma patients. Targeting CENPM suppresses cutaneous melanoma growth and mobility by inactivating AKT pathway, indicating its potential as a treatment target.

Critically, the 3D microenvironment induced a more aggressive phenotype, characterized by upregulated expression of the BRAF V600E oncogene and the induction of epithelial-mesenchymal transition (EMT), and conferred significantly increased resistance to both cisplatin and vemurafenib. These findings indicate that our tissue-specific, TAS-based 3D model successfully recapitulates key pathophysiological hallmarks of thyroid cancer, representing a more clinically relevant and predictive platform for investigating tumor mechanisms and for the preclinical evaluation of novel therapeutic agents.

Despite substantial advances, secondary mutations and reactivation of oncogenic signaling remain major challenges. This narrative review integrates data from clinical, preclinical, and real-world studies to update the current understanding of targeted therapies in cutaneous melanoma and highlight ongoing research aimed at overcoming resistance and optimizing personalized treatment strategies.

Moreover, the PLK1/BACH1 axis confers resistance to Vemurafenib, a BRAFV600E inhibitor, in melanoma. In light of this finding, we attempted an innovative pharmacological combination targeting both BRAFV600E and PLK1, identifying a synergistic efficiency to this approach to suppress tumor growth. Overall, we have discovered a novel function of PLK1 that is independent of the cell cycle, which could pave new ways for melanoma therapies.

This study evaluated PRI-724, a CBP/β-catenin inhibitor, in patient-derived drug-naïve melanoma cells and their trametinib- or vemurafenib-resistant counterparts. The results of the study point to the potential of PRI-724 as a chemotherapeutic agent for the treatment of melanoma. Its efficacy might depend on CBP/β-catenin transcriptional activity in melanoma cells, and further evaluation of this signaling with survivin as a biomarker is therefore warranted.

A combination of vemurafenib, cetuximab combined with camrelizumab exhibited manageable adverse reactions and efficacy in BRAF V600E-mutated/MSS patients with metastatic colorectal cancer who progressed after standard treatment. This is a pilot study and a larger phase II trials is planned to validate the findings. (ClinicalTrials.gov ID: NCT05019534).

Moreover, we found that genetic depletion of TRMU in IGR37xp cells results in diminished oxidative phosphorylation and resensitizes IGR37xp cells to vemurafenib. Together, we uncovered a role of TRMU in conferring vemurafenib resistance in melanoma through modulating oxidative phosphorylation.

Additionally, investigation of the VEGFR-2 inhibitory activity of the ten promising compounds revealed that 4c, 4d and 6i displayed promising VEGFR-2 inhibition (IC50 = 0.144, 0.105, and 0.072 μM, respectively) compared to sorafenib (IC50 = 0.081 μM). Moreover, 4c inhibited BRAFWT and BRAFV600E kinases (IC50 = 0.201 and 0.101 μM, respectively) relative to vemurafenib (IC50 = 0.156 and 0.063 μM, respectively)...Moreover, evaluation of the effect of 4c on apoptotic markers in the mentioned cells indicated an increase in the Bax/Bcl-2 ratio by 28.12-fold along with upregulation of caspases-3 and -9 by 7.40- and 5.63-fold, respectively, in addition to anti-migratory effect. Molecular docking study of the most promising derivatives revealed a common binding pattern in the binding site of the target kinases that extends from the hinge region through the gate area towards the allosteric back pocket interacting with the key amino acids in a type II inhibitor-like binding pattern.

Given USP7's role in oxidative stress and ferroptosis, we examined its involvement and found that P5091 induced ferroptosis via reactive oxygen species (ROS) elevation, glutathione peroxidase 4 (GPX4) downregulation, and elevated lipid peroxidation. These findings demonstrate that USP7 inhibition by P5091 enhances PLX4032 efficacy by promoting tumor suppression and ferroptosis in BRAFV600E-mutant thyroid cancer, offering a promising strategy to overcome resistance.

P2, N=17, Completed, H. Lee Moffitt Cancer Center and Research Institute | Active, not recruiting --> Completed

Mechanistically, LINC01198 directly associates with TAOK1/2 to inhibit TAOK1/2 phosphorylation and thereby elicits Hippo signaling through TAOK/LATS axis, which redistributes YAP/TAZ into nucleus and promotes the expression and secretion of IL-1β to support vemurafenib resistance in melanoma. Our study not only identifies LINC01198 as a potent indicator and critical factor for driving vemurafenib resistance, but also suggests a series of therapeutic targets for tackling vemurafenib resistance in melanoma.

Monotherapies such as vemurafenib and dabrafenib, which target a mutant form of BRAF kinase, become ineffective within six months of treatment. The PDCs crossed membranes with the drug cargo attached and killed melanoma cells with similar or improved activity relative to the free drug. The choice of peptide carrier impacted overall PDC potency and selectivity, and we identified an optimal membrane-active carrier peptide where the Vem-containing PDC exhibited activity against both drug-naı̈ve and drug-resistant melanoma cells while maintaining selectivity over noncancer cells.