This PEITC effect could be demonstrated in two further dabrafenib-resistant cell lines, WM164D and 451LuP. These results suggest that the altered redox status is linked to compromised mitochondria and is associated with the development of BRAFi resistance, rendering cells exquisitely sensitive to the actions of selective ROS-inducing therapeutics.

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.

Preclinical studies show that pharmacological inducers, including vitamin C, tenacissoside H, neferine, curcumin, and shikonin, as well as targeted agents such as dabrafenib and anlotinib, can trigger or synergize with ferroptosis. Although systemic toxicity and resistance remain obstacles, biomarker-driven selection and drug repurposing offer promise. Ferroptosis represents a mechanistically distinct and clinically exploitable pathway for ATC.

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.

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).

P2, N=96, Recruiting, University of California, San Francisco | Not yet recruiting --> Recruiting

P1, N=6, Recruiting, City of Hope Medical Center | Trial completion date: Oct 2025 --> Feb 2026 | Trial primary completion date: Oct 2025 --> Feb 2026

P4, N=100, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2027 --> Dec 2030 | Trial primary completion date: Dec 2027 --> Dec 2029

P2, N=96, Not yet recruiting, University of California, San Francisco | Trial completion date: Dec 2031 --> Mar 2032 | Initiation date: Oct 2025 --> Dec 2025 | Trial primary completion date: Dec 2031 --> Mar 2032

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.