Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF -mutant thyroid carcinomas Journal Article


Authors: Montero-Conde, C.; Ruiz-Llorente, S.; Domínguez, J. M.; Knauf, J. A.; Viale, A.; Sherman, E. J.; Ryder, M.; Ghossein, R. A.; Rosen, N.; Fagin, J. A.
Article Title: Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF -mutant thyroid carcinomas
Abstract: The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF -mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. In contrast to melanomas, inhibition of mitogen-activated protein kinase (MAPK) signaling by PLX4032 is transient in thyroid and colorectal cancer cells. The rebound in extracellular signal-regulated kinase (ERK) in thyroid cells is accompanied by increased HER3 signaling caused by induction of ERBB3 (HER3) transcription through decreased promoter occupancy by the transcriptional repressors C-terminal binding protein 1 and 2 and by autocrine secretion of neuregulin-1 (NRG1). The HER kinase inhibitor lapatinib prevents MAPK rebound and sensitizes BRAF -mutant thyroid cancer cells to RAF or MAP-ERK kinase inhibitors. This provides a rationale for combining ERK pathway antagonists with inhibitors of feedbackreactivated HER signaling in this disease. The determinants of primary resistance to MAPK inhibitors vary between cancer types, due to preferential upregulation of specific receptor tyrosine kinases, and the abundance of their respective ligands. Significance: Thyroid cancer cell lines with mutant BRAF are resistant to PLX4032. RAF inhibitors transiently inhibit the ERK pathway and de-repress HER3 transcription. In the context of constitutive NRG1 secretion, this results in an ERK and AKT rebound that diminishes the antitumor effects of RAF inhibitors, which is overcome by combination with lapatinib. © 2013 American Association for Cancer Research.
Keywords: cancer survival; protein expression; protein phosphorylation; unclassified drug; nonhuman; antineoplastic agents; neoplasms; animal cell; mouse; animal tissue; cell cycle; disease association; reverse transcription polymerase chain reaction; gene expression; gene expression profiling; cell growth; mitogen activated protein kinase inhibitor; rna interference; genetic transcription; receptor, epidermal growth factor; antineoplastic activity; protein tyrosine kinase; cancer resistance; protein kinase inhibitors; chromatin immunoprecipitation; western blotting; immunoblotting; thyroid carcinoma; real time polymerase chain reaction; upregulation; epidermal growth factor receptor 3; ic 50; lapatinib; short hairpin rna; proto-oncogene proteins b-raf; b raf kinase inhibitor; neu differentiation factor; vemurafenib; n (2, 3 dihydroxypropoxy) 3, 4 difluoro 2 (2 fluoro 4 iodoanilino) benzamide
Journal Title: Cancer Discovery
Volume: 3
Issue: 5
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2013-05-01
Start Page: 520
End Page: 533
Language: English
DOI: 10.1158/2159-8290.cd-12-0531
PROVIDER: scopus
PMCID: PMC3651738
PUBMED: 23365119
DOI/URL:
Notes: --- - Cited By (since 1996):1 - "Export Date: 3 June 2013" - "Source: Scopus"
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