journal contribution
posted on 2023-04-03, 19:48 authored by Mark Lee, Brian R. Untch, Bin Xu, Ronald Ghossein, Catherine Han, Fengshen Kuo, Cristina Valero, Zaineb Nadeem, Neal Patel, Vladimir Makarov, Snjezana Dogan, Richard J. Wong, Eric J. Sherman, Alan L. Ho, Timothy A. Chan, James A. Fagin, Luc G.T. Morris Supplemental Figure 1. Increased clonal heterogeneity in anaplastic metastases (ATC Met 1, 5 clones Supplemental Figure 2. Copy-number alterations for the pre-vemurafenib papillary thyroid carcinoma sample Supplemental Figure 3. Differentially expressed gene analyses comparing pre-treatment PTC sample and ATC metastases in MSK-THY1. Supplemental Figure 4. Prevalence of genetic alterations linked to BRAF inhibitor resistance and/or ATC pathogenesis in primary TCGA PTCs and metastatic/recurrent PTCs, PDTCs, and ATCs sequenced by MSK-IMPACT. Supplemental Figure 5. Histology and immunohistochemical studies for MSK-THY6. Supplemental Figure 6. Mutational landscape of tumors that underwent dedifferentiation subsequent to BRAF inhibitor targeted therapy with vemurafenib or dabrafenib.
Funding
Fundación Alfonso Martín Escudero
NIH
Sebastian Nativo Fund
Jayme and Peter Flowers Fund
Pershing Square Sohn Cancer Research Foundation
PaineWebber Chair
Stand Up To Cancer
STARR Cancer Consortium
NIH Cancer Center Support Grant
History
ARTICLE ABSTRACT
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.
The possibility that thyroid cancer dedifferentiation may be attributed to selective pressure applied by BRAF inhibitor–targeted therapy should be investigated further.
