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.

The authors discuss adverse event management and the implications for integration into routine clinical practice. Clinicians caring for patients with low-grade serous ovarian carcinoma can use the drug knowledge and evidence outlined in this review to assist with implementing avutometinib and defactinib therapy.

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.

In vivo studies demonstrated that combination therapy reduced tumor volume without causing systemic toxicity, accompanied by decreased proliferation markers (PCNA and Ki-67), increased apoptotic marker (cleaved caspase-3), and decreased B7-H3 expression in tumor tissues. These results suggest that JI-CJ002 may enhance the antitumor activity of dabrafenib, accompanied by modulation of oncogenic pathways.

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

P2, N=36, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

P1, N=6, Recruiting, City of Hope Medical Center | Trial completion date: Feb 2026 --> Oct 2027 | Trial primary completion date: Feb 2026 --> Oct 2027

P2, N=50, Recruiting, Emory University | Trial completion date: Sep 2028 --> Sep 2029 | Trial primary completion date: Mar 2028 --> Mar 2029

P4, N=100, Recruiting, Novartis Pharmaceuticals | Trial completion date: Dec 2030 --> Dec 2032 | Trial primary completion date: Dec 2029 --> Dec 2032

Four protein kinase inhibitors, R547, GDC-0879, JNJ-7706621 and ABT-869 were found to bind hPIP5K1α via a stable complex formation. The hit molecules display favorable ADME properties and are predicted to be non-carcinogenic. The hit molecules in particular R547, have better binding free energies compared to reference molecule, ISA-2011B.

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.