Genomic and Transcriptomic Correlates of Thyroid Carcinoma Evolution after BRAF Inhibitor Therapy
| Autor: | Timothy A. Chan, Eric J. Sherman, Catherine Han, Zaineb Nadeem, Vladimir Makarov, Alan L. Ho, James A. Fagin, Mark Lee, Bin Xu, Richard J. Wong, Snjezana Dogan, Neal Patel, Cristina Valero, Ronald Ghossein, Luc G. T. Morris, Fengshen Kuo, Brian R. Untch |
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| Rok vydání: | 2022 |
| Předmět: |
Male
Proto-Oncogene Proteins B-raf Cancer Research endocrine system diseases medicine.medical_treatment Article Targeted therapy Thyroid carcinoma Transcriptome Tumor Microenvironment Humans Medicine Thyroid Neoplasms Protein Kinase Inhibitors Molecular Biology Thyroid cancer Exome sequencing PI3K/AKT/mTOR pathway Tumor microenvironment business.industry Thyroid Genomics medicine.disease medicine.anatomical_structure Oncology Cancer research Female business |
| Zdroj: | Mol Cancer Res |
| ISSN: | 1557-3125 1541-7786 |
| Popis: | Targeted inhibition of BRAF V600E achieves tumor control in a subset of advanced thyroid tumors. Nearly all tumors develop resistance, and some have been observed to subsequently undergo dedifferentiation. The molecular alterations associated with thyroid cancer dedifferentiation in the setting of BRAF inhibition are unknown. We analyzed targeted next-generation sequencing data from 639 advanced, recurrent and/or metastatic thyroid carcinomas, including 15 tumors that were treated with BRAF inhibitor drugs and had tissue sampled during or posttreatment, 8 of which had matched pretherapy samples. Pre- and posttherapy tissues from one additional patient were profiled with whole-exome sequencing and RNA expression profiling. Mutations in genes comprising the SWI/SNF chromatin remodeling complex and the PI3K–AKT–mTOR, MAPK, and JAK–STAT pathways all increased in prevalence across more dedifferentiated thyroid cancer histologies. Of 7 thyroid cancers that dedifferentiated after BRAF inhibition, 6 had mutations in these pathways. These mutations were mostly absent from matched pretreatment samples and were rarely detected in tumors that did not dedifferentiate. Additional analyses in one of the vemurafenib-treated tumors before and after anaplastic transformation revealed the emergence of an oncogenic PIK3CA mutation, activation of ERK signaling, dedifferentiation, and development of an immunosuppressive tumor microenvironment. These findings validate earlier preclinical data implicating these genetic pathways in resistance to BRAF inhibitors, and suggest that genetic alterations mediating acquired drug resistance may also promote thyroid tumor dedifferentiation. Implications: The possibility that thyroid cancer dedifferentiation may be attributed to selective pressure applied by BRAF inhibitor–targeted therapy should be investigated further. |
| Databáze: | OpenAIRE |
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