SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies

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 , or in mouse BRAF -mutant tumors promotes disease progression and decreased survival, associated with l...

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Veröffentlicht in:Cancer discovery 2021-05, Vol.11 (5), p.1158-1175
Hauptverfasser: Saqcena, Mahesh, Leandro-Garcia, Luis Javier, Maag, Jesper L V, Tchekmedyian, Vatche, Krishnamoorthy, Gnana P, Tamarapu, Prasanna P, Tiedje, Vera, Reuter, Vincent, Knauf, Jeffrey A, de Stanchina, Elisa, Xu, Bin, Liao, Xiao-Hui, Refetoff, Samuel, Ghossein, Ronald, Chi, Ping, Ho, Alan L, Koche, Richard P, Fagin, James A
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Sprache:eng
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Zusammenfassung: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 , or in mouse BRAF -mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAF -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 -mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.CD-20-0735