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Vemurafenib-resistance via de novo RBM genes mutations and chromosome 5 aberrations is overcome by combined therapy with palbociclib in thyroid carcinoma with BRAFV600E
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Zeus A. Antonello1,2, Nancy Hsu3, Manoj Bhasin4, Giovanni Roti5, Mukta Joshi4, Paul Van Hummelen6, Emily Ye1,2, Agnes S. Lo7, S. Ananth Karumanchi7, Christine R. Bryke3 and Carmelo Nucera1,2
1 Laboratory of human thyroid cancers preclinical and translational research, Division of Experimental Pathology, Cancer Research Institute, Cancer Center, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
2 Department of Pathology, Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
3 Cytogenetics Laboratory, Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
4 Bioinformatic and Systems Biology Unit, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
5 Department of Medicine and Surgery, University of Parma, Parma, Italy
6 Center for Cancer Genome Discovery, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
7 Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Carmelo Nucera, email:
Keywords: papillary thyroid cancer preclinical model, BRAFV600E, chromosome 5, combined therapy with vemurafenib and palbociclib, drug resistance
Received: July 14, 2017 Accepted: August 15, 2017 Published: September 24, 2017
Purpose: Papillary thyroid carcinoma (PTC) is the most frequent endocrine tumor. BRAFV600E represents the PTC hallmark and is targeted with selective inhibitors (e.g. vemurafenib). Although there have been promising results in clinical trials using these inhibitors, most patients develop resistance and progress. Tumor clonal diversity is proposed as one mechanism underlying drug resistance. Here we have investigated mechanisms of primary and secondary resistance to vemurafenib in BRAFWT/V600E–positive PTC patient-derived cells with P16-/- (CDKN2A-/-).
Experimental Design: Following treatment with vemurafenib, we expanded a sub-population of cells with primary resistance and characterized them genetically and cytogenetically. We have used exome sequencing, metaphase chromosome analysis, FISH and oligonucleotide SNP-microarray assays to assess clonal evolution of vemurafenib-resistant cells. Furthermore, we have validated our findings by networks and pathways analyses using PTC clinical samples.
Results: Vemurafenib-resistant cells grow similarly to naïve cells but are refractory to apoptosis upon treatment with vemurafenib, and accumulate in G2-M phase. We find that vemurafenib-resistant cells show amplification of chromosome 5 and de novo mutations in the RBM (RNA-binding motifs) genes family (i.e. RBMX, RBM10). RBMX knockdown in naïve-cells contributes to tetraploidization, including expansion of clones with chromosome 5 aberrations (e.g. isochromosome 5p). RBMX elicits gene regulatory networks with chromosome 5q cancer-associated genes and pathways for G2-M and DNA damage-response checkpoint regulation in BRAFWT/V600E-PTC. Importantly, combined therapy with vemurafenib plus palbociclib (inhibitor of CDK4/6, mimicking P16 functions) synergistically induces stronger apoptosis than single agents in resistant-cells and in anaplastic thyroid tumor cells harboring the heterozygous BRAFWT/V600E mutation.
Conclusions: Critically, our findings suggest for the first time that targeting BRAFWT/V600E and CDK4/6 represents a novel therapeutic strategy to treat vemurafenib-resistant or vemurafenib-naïve radioiodine-refractory BRAFWT/V600E-PTC. This combined therapy could prevent selection and expansion of aggressive PTC cell sub-clones with intrinsic resistance, targeting tumor cells either with primary or secondary resistance to BRAFV600E inhibitor.
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