P4, N=0, Withdrawn, SRH Wald-Klinikum Gera GmbH | N=101 --> 0 | Not yet recruiting --> Withdrawn

We have identified a small molecule produced by a marine sponge as being able to inhibit PTCH1 efflux activity and increase the efficacy of vemurafenib treatment on BRAF-mutated melanoma cells in vitro and in vivo in mice. We found that inhibiting PTCH1 drug efflux activity significantly increased the cytotoxic effect of chemotherapies such as doxorubicin and docetaxel in three TNBC cell lines. Overall, our findings suggest that PTCH1 plays a role in the resistance of TNBC cells to chemotherapy, and that using a PTCH1 efflux inhibitor during neoadjuvant or adjuvant therapy could enhance the efficacy of treatment against PTCH1-expressing TNBC, while preventing treatment resistance, relapse, and metastasis formation.

P2, N=25, Active, not recruiting, Fondazione Policlinico Universitario Agostino Gemelli IRCCS | Recruiting --> Active, not recruiting

Vemurafenib increases miR-31-5p in keratinocyte-derived exosomes, which suppresses ALKBH1 and elevates RNA m6A in melanoma cells, thereby promoting proliferation and reducing vemurafenib sensitivity. Targeting the miR-31-5p/ALKBH1 axis and m6A modification may offer a potential therapeutic strategy to enhance vemurafenib sensitivity in BRAFV600E melanoma cells.

P1, N=24, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | N=15 --> 24 | Trial completion date: Jun 2027 --> Jun 2028 | Trial primary completion date: Jun 2026 --> Jun 2027

KSR1 knockdown did not substantially affect ppERK responses to Type I½ RAF inhibitor (Encorafenib) in both cell types, whereas ppERK sensitivity slightly decreased for Type II RAFi (TAK-632) in MCF7 cells, aligning with simulations. The efficacy of MEKi (Cobimetinib) slightly increased in MCF7 cells following KSR1 knockdown but slightly decreased in PSN1 cells where higher MEKi concentrations were required to suppress ERK signaling, as predicted by the model. Our computational models predict, and experiments validate that in RAS-mutant cells, two conformation-specific RAF inhibitors used in combination suppress the ERK pathway more effectively than a combination of MEK and RAF inhibitors irrespective of KSR1 levels.

P2, N=24, Active, not recruiting, Providence Health & Services | Trial completion date: Jan 2027 --> Dec 2028 | Trial primary completion date: Jan 2026 --> Dec 2027

P=N/A, N=50, Active, not recruiting, Pierre Fabre Ltd | Recruiting --> Active, not recruiting

We report here a patient on encorafenib who developed numerous new pigmented lesions within 3 weeks of therapy...This case underscores that BRAF inhibition may enhance PRAME expression in benign melanocytic nevi, potentially through mechanisms involving mitogen-activated protein kinase (MAPK) activation, altered Erk phosphorylation, or disruption of retinoic acid (RA) signaling. This case also brings awareness to the potential of medication-induced PRAME expression and encourages both dermatologists and dermatopathologists to avoid overdiagnosis as PRAME continues to gain prominence as a diagnostic biomarker.

Through integrated transcriptomic and metabolomic analyses, we demonstrate that BRAFi by vemurafenib (PLX4032) significantly enhances FAO in thyroid cancer cells. The pharmacological inhibition of FAO via thioridazine (Thio) synergizes with BRAFi to suppress tumor growth in vitro, in vivo and in a patient-derived organoid...Consistently, functional studies confirm RUNX1's oncogenic role, as its knockdown reduces cell proliferation, migration, and invasion. In conclusion, our work reveals a metabolic-epigenetic axis underlying adaptive response to BRAFi and identifies RUNX1 as a novel oncogene in thyroid cancer.