Research Perspectives:

Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation

Mark Lee and Luc GT Morris _

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Mark Lee1 and Luc GT Morris2

1 Department of Otolaryngology-Head and Neck Surgery, New York Presbyterian Hospital, New York, NY 10032, USA

2 Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

Correspondence to:

Luc GT Morris, email: [email protected]

Keywords: thyroid cancer; drug resistance; anaplastic transformation; BRAF inhibitors; PIK3CA

Received: October 31, 2023     Accepted: December 08, 2023     Published: January 24, 2024

Copyright: © 2024 Lee and Morris. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor 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 tumor dedifferentiation. DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling 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 tumor 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 tumor 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-tumor immune activity with these combinations.

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