A new research perspective was published in Oncotarget's Volume 15 on January 24, 2024, entitled, “Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.”

In this new paper, researchers Mark Lee and Luc GT Morris from New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center discuss thyroid cancer.

A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy.

Tumours harbouring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumour response is often short-lived due to multiple compensatory resistance mechanisms. 

“One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumour dedifferentiation.” 

DNA sequencing and RNA expression profiling show that thyroid tumours that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumour dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodelling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1).

Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumour control illustrates the complex and multifactorial nature of these compensatory mechanisms.

Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumour dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. 

“Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumour immune activity with these combinations.”

Source: Impact Journals LLC