Understanding and overcoming innate and acquired MAPK inhibition resistance in anaplastic thyroid cancer - PubMed
2 days ago
- #type II RAF inhibitor
- #MAPK resistance
- #anaplastic thyroid cancer
- Anaplastic thyroid cancer (ATC) is highly lethal, and resistance to initial targeted therapies like dabrafenib with trametinib often develops.
- Resistance mechanisms involve reactivation of the MAPK pathway and proliferation of immunosuppressive macrophages, as shown through genomic and transcriptomic sequencing.
- ATC cell lines show sensitivity to the type II RAF inhibitor naporafenib, which targets EphA2-mediated MAPK signaling and overcomes innate and acquired resistance in models.
- Acquired resistance to naporafenib can occur via compensatory mutations in MAST1, highlighting a potential resistance mechanism for future study.
- Clinical investigation of type II RAF inhibitors, such as naporafenib, is supported for treating ATC, especially in cases of resistance to existing therapies.