Oncotarget

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Metastasis-associated MCL1 and P16 copy number alterations dictate resistance to vemurafenib in a BRAFV600E patient-derived papillary thyroid carcinoma preclinical model

Mark Duquette, Peter M. Sadow, Amjad Husain, Jennifer N. Sims, Zeus A. Antonello, Andrew H. Fischer, Chen Song, Elena Castellanos-Rizaldos, G. Mike Makrigiorgos, Junichi Kurebayashi, Vania Nose, Paul Van Hummelen, Roderick T. Bronson, Michelle Vinco, Thomas J. Giordano, Dora Dias-Santagata, Pier Paolo Pandolfi and Carmelo Nucera _

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Oncotarget. 2015; 6:42445-42467. https://doi.org/10.18632/oncotarget.6442

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Abstract

Mark Duquette1, Peter M. Sadow2, Amjad Husain3,*, Jennifer N. Sims1,*, Zeus A. Antonello1,*, Andrew H. Fischer4, Chen Song5, Elena Castellanos-Rizaldos5, G. Mike Makrigiorgos5, Junichi Kurebayashi6, Vania Nose2, Paul Van Hummelen7, Roderick T. Bronson8, Michelle Vinco9, Thomas J. Giordano9, Dora Dias-Santagata10, Pier Paolo Pandolfi11 and Carmelo Nucera1,3

1 Laboratory of Human Thyroid Cancers Preclinical and Translational Research, Division of Cancer Biology and Angiogenesis, Cancer Research Institute (CRI), Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

2 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, MA, Boston, USA

3 Department of Pathology, Center for Vascular Biology Research (CVBR), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

4 Department of Pathology, University of Massachusetts, Worcester, MA, USA

5 Department of Radiation Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

6 Department of Breast and Thyroid Surgery, Kawasaki Medical School, Kurashiki, Japan

7 Center for Cancer Genome Discovery (CCGD), Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

8 Rodent Histopathology Unit, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA

9 Department of Pathology, University of Michigan, Ann Harbor, MI, USA

10 Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

11 Division of Cancer Genetics, Cancer Research Institute (CRI), Department of Medicine and Department of Pathology, Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

* These authors equally contributed to this work

Correspondence to:

Carmelo Nucera, email:

Keywords: BRAFV600E papillary thyroid cancer pre-clinical model, vemurafenib resisatnce, MCL1 and P16/CDKN2A somatic copy number, microenvironment

Received: September 06, 2015 Accepted: October 22, 2015 Published: November 30, 2015

Abstract

BRAFV600E mutation exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC).  Although BRAFV600E inhibitors are available, lack of response has been frequently observed.  To study the mechanism underlying intrinsic resistance to the mutant BRAFV600E selective inhibitor vemurafenib, we established short-term primary cell cultures of human metastatic/recurrent BRAFV600E-PTC, intrathyroidal BRAFV600E-PTC, and normal thyroid (NT). We also generated an early intervention model of human BRAFV600E-PTC orthotopic mouse. We find that metastatic BRAFV600E-PTC cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAFWT-PTC cells, and show a higher rate of invasion.  We further show that vemurafenib therapy significantly suppresses these aberrant functions in non-metastatic BRAFV600E-PTC cells but lesser in metastatic BRAFV600E-PTC cells as compared to vehicle treatment. These results concur with similar folds of down-regulation of tumor microenvironment–associated pro-metastatic molecules, with no effects in BRAFWT-PTC and NT cells. Our early intervention preclinical trial shows that vemurafenib delays tumor growth in the orthotopic BRAFWT/V600E-PTC mice. Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss of CDKN2A (P16, chromosome 9p) in metastatic BRAFV600E-PTC cells which are associated with resistance to vemurafenib treatment. Critically, we demonstrate that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic BRAFV600E-PTC cell death and ameliorates response to vemurafenib treatment as compared to single agent treatment. In conclusion, short-term PTC and NT cultures offer a predictive model for evaluating therapeutic response in patients with PTC. Our PTC pre-clinical model suggests that combined targeted therapy might be an important therapeutic strategy for metastatic and refractory BRAFV600E-positive PTC.


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