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Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers
Jeffrey A. Knauf, … , Ronald Ghossein, James A. Fagin
Jeffrey A. Knauf, … , Ronald Ghossein, James A. Fagin
Published July 10, 2018
Citation Information: J Clin Invest. 2018;128(9):4086-4097. https://doi.org/10.1172/JCI120966.
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Research Article Oncology

Hgf/Met activation mediates resistance to BRAF inhibition in murine anaplastic thyroid cancers

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Abstract

Anaplastic thyroid carcinomas (ATCs) have a high prevalence of BRAF and TP53 mutations. A trial of vemurafenib in nonmelanoma BRAFV600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden. To explore the mechanisms mediating acquired resistance to BRAF blockade, we generated mice with thyroid-specific deletion of p53 and dox-dependent expression of BRAFV600E, 50% of which developed ATCs after dox treatment. Upon dox withdrawal there was complete regression in all mice, although recurrences were later detected in 85% of animals. The relapsed tumors had elevated MAPK transcriptional output, and retained responses to the MEK/RAF inhibitor CH5126766 in vivo and in vitro. Whole-exome sequencing identified recurrent focal amplifications of chromosome 6, with a minimal region of overlap that included Met. Met-amplified recurrences overexpressed the receptor as well as its ligand Hgf. Growth, signaling, and viability of Met-amplified tumor cells were suppressed in vitro and in vivo by the Met kinase inhibitors PF-04217903 and crizotinib, whereas primary ATCs and Met-diploid relapses were resistant. Hence, recurrences are the rule after BRAF suppression in murine ATCs, most commonly due to activation of HGF/MET signaling, which generates exquisite dependency to MET kinase inhibitors.

Authors

Jeffrey A. Knauf, Kathleen A. Luckett, Kuen-Yuan Chen, Francesca Voza, Nicholas D. Socci, Ronald Ghossein, James A. Fagin

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Figure 1

BRAFV600E-driven mouse model of ATC.

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BRAFV600E-driven mouse model of ATC.
(A) Genetic schema of mouse model o...
(A) Genetic schema of mouse model of dox-inducible BRAFV600E-driven ATCs. Left: LSL-rtTA-ires-GFP construct targeted to the Rosa allele, which only expresses rtTA after Cre excision. Expression of rtTA transduces expression of a tetO-driven myc-tagged BRAFV600E in the presence of dox. Right: Exons 2–10 of Trp53 are flanked by loxP sites (red arrows) in Trp53fl mice. Thyroid-specific inactivation of Trp53 and expression of rtTA is achieved by crosses with TPO-Cre mice. (B) ATC-free survival of TPO-Cre negative (normal), TPO-Cre/LSL-rtTA-GFP/tetO-BRAFV600E (BRAF), TPO-Cre/Trp53fl/fl (p53), and BRAF/p53 mice after switching to dox-impregnated chow. Each cohort consisted of at least 9 mice. (C) Left: H&E staining of thyroid tumor sections from TPO-Cre/LSL-rtTA-GFP/tetO-BRAFV600E/Trp53fl/fl (BRAF/p53) mouse on dox showing an ATC with giant cells (double arrow) and spindle-shaped cells (single arrow). Scale bar, 50 μm. Middle: Representative H&E staining of ATC remnant 3 weeks after dox withdrawal showing marked fibrosis with small foci of thyroid cells with benign morphology (arrow). Scale bar, 20 μm. Right: ATCs that recurred after genetic inhibition of BRAFV600E (arrow: spindle-shaped tumor cell). Scale bar, 50 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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