Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer, frequently characterized by mutations in the BRAF gene, specifically BRAFV600E. This mutation activates the ERK1/2 pathway, promoting tumor growth and inhibiting apoptosis. Although many PTC patients undergo surgical resection, concerns arise due to the potential long-term side effects of maintenance therapy, particularly since most patients are under 50 years old. While mutant-selective BRAF inhibitors (BRAFi) like vemurafenib have shown effectiveness in treating metastatic melanoma, their efficacy in mutant BRAF PTC patients has been limited.

In this study, we evaluated the therapeutic response to BRAFi in various human PTC cell lines and freshly obtained patient samples. The responses were heterogeneous, and multi-omic analyses of BRAFi-sensitive and -resistant mutant BRAF PTC revealed an overrepresentation of stress response pathways and a lack of compensatory RTK activation in resistant samples—factors that may contribute to innate resistance. Notably, resistant cell lines and patient samples exhibited signs of failed apoptosis, characterized by sublethal caspase activation and DNA damage.

Further investigation suggests that these failed apoptotic states may be linked to a phenomenon called “minority mitochondrial outer membrane permeabilization (MOMP),” which involves fragmented and porous mitochondria and is associated with cancer aggressiveness. We discovered that cells with minority MOMP-like characteristics rely on the apoptotic regulator Mcl-1 for survival. Treatment with the Mcl-1 inhibitor AZD5991 effectively induced cell death in resistant cells. Additionally, PI3K/AKT inhibitors sensitized resistant cells to BRAFi, partly by reducing Mcl-1 levels. These findings suggest that minority MOMP may play a role in intrinsic drug resistance and highlight the potential therapeutic benefit of targeting Mcl-1 in mutant BRAF PTC.