Journal
CANCER DISCOVERY
Volume 11, Issue 5, Pages 1158-1175Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-20-0735
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Funding
- NIH [CA50706-23, CA184724-01A1, DK-15070]
- Cycle for Survival
- Geoffrey Beene Cancer Research Center
- NCI Thyroid Cancer SPORE [P50 CA 172012-01]
- Translational Research Oncology Training program [5T32CA160001]
- Celldex Therapeutics
- NCI Cancer Center Support Grant (CCSG) [P30 CA08748]
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- MSKCC Research Animal Resource Center
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Mutations in SWI/SNF genes are common in thyroid cancers, leading to disease progression and decreased survival. BRAF(V600E)-mutant thyroid cancers exhibit decreased lineage transcription factor expression and impaired iodine incorporation, which can be rescued by MAPK inhibition. Loss of SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that is insensitive to the redifferentiation effects of MAPK blockade.
Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of Arid1a, Arid2, or Smarcb1 in mouse BRAF(V600E)-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAF(V600E)-mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor-based redifferentiation therapies. SIGNIFICANCE: Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in BRAF-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade.
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