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.

BRAF V600E is associated with inferior prognoses compared to BRAF WT in early-stage CC. This finding will help optimize trial design for this population.

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.

P1/2, N=38, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

P2, N=24, Active, not recruiting, Providence Health & Services | Trial completion date: Oct 2027 --> Jan 2027 | Trial primary completion date: Oct 2025 --> Jan 2026

P2, N=98, Completed, Pfizer | Active, not recruiting --> Completed

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.