Shohreh Varmeh1, Pierre Vanden Borre1, Viswanath Gunda1, Eran Brauner1, Tammy Holm1, Yangun Wang2, Ruslan Ilyasovich Sadreyev3, Sareh Parangi4. 1. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 2. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA; Department of Genetics, Harvard Medical School, Boston, MA. 3. Department of Molecular Biology, Massachusetts General Hospital, Boston, MA; Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA. 4. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA. Electronic address: sparangi@partners.org.
Abstract
BACKGROUND: Investigating BRAF((V600E)) inhibitors (BRAFi) as a strategy to treat patients with aggressive thyroid tumors harboring the BRAF((V600E)) mutant currently is in progress, and drug resistance is expected to pose a challenge. MicroRNAs (miRNAs) are involved in development of resistance to a variety of drugs in different malignancies. METHODS: miRNA expression profiles in the human anaplastic thyroid cancer cell line (8505c) were compared with its PLX4720-resistant counterpart (8505c-R) by the use of Illumina deep sequencing. We conducted a functional annotation and pathway analysis of the putative and experimentally validated target genes of the significantly altered miRNAs. RESULTS: We identified 61 known and 2 novel miRNAs whose expression was altered greatly in 8505c-R. Quantitative reverse-transcription polymerase chain reaction validated altered expression of 7 selected miRNAs in 8505c-R and BCPAP-R (PLX4720-resistant papillary thyroid cancer cell line). We found 14 and 25 miRNAs whose expression levels changed substantially in 8505c and 8505c-R, respectively, after treatment with BRAFi. The mitogen-activated protein kinase and phosphatidylinositol 3-kinase-AKT pathways were among the prominent targets of many of the deregulated miRNAs. CONCLUSION: We have identified a number of miRNAs that could be used as biomarkers of resistance to BRAFi in patients with thyroid cancer. In addition, these miRNAs can be explored as potential therapeutic targets in combination with BRAFi to overcome resistance.
BACKGROUND: Investigating BRAF((V600E)) inhibitors (BRAFi) as a strategy to treat patients with aggressive thyroid tumors harboring the BRAF((V600E)) mutant currently is in progress, and drug resistance is expected to pose a challenge. MicroRNAs (miRNAs) are involved in development of resistance to a variety of drugs in different malignancies. METHODS: miRNA expression profiles in the human anaplastic thyroid cancer cell line (8505c) were compared with its PLX4720-resistant counterpart (8505c-R) by the use of Illumina deep sequencing. We conducted a functional annotation and pathway analysis of the putative and experimentally validated target genes of the significantly altered miRNAs. RESULTS: We identified 61 known and 2 novel miRNAs whose expression was altered greatly in 8505c-R. Quantitative reverse-transcription polymerase chain reaction validated altered expression of 7 selected miRNAs in 8505c-R and BCPAP-R (PLX4720-resistant papillary thyroid cancer cell line). We found 14 and 25 miRNAs whose expression levels changed substantially in 8505c and 8505c-R, respectively, after treatment with BRAFi. The mitogen-activated protein kinase and phosphatidylinositol 3-kinase-AKT pathways were among the prominent targets of many of the deregulated miRNAs. CONCLUSION: We have identified a number of miRNAs that could be used as biomarkers of resistance to BRAFi in patients with thyroid cancer. In addition, these miRNAs can be explored as potential therapeutic targets in combination with BRAFi to overcome resistance.
Authors: Ryan B Corcoran; Hiromichi Ebi; Alexa B Turke; Erin M Coffee; Michiya Nishino; Alexandria P Cogdill; Ronald D Brown; Patricia Della Pelle; Dora Dias-Santagata; Kenneth E Hung; Keith T Flaherty; Adriano Piris; Jennifer A Wargo; Jeffrey Settleman; Mari Mino-Kenudson; Jeffrey A Engelman Journal: Cancer Discov Date: 2012-01-16 Impact factor: 39.397
Authors: Cristina Montero-Conde; Sergio Ruiz-Llorente; Jose M Dominguez; Jeffrey A Knauf; Agnes Viale; Eric J Sherman; Mabel Ryder; Ronald A Ghossein; Neal Rosen; James A Fagin Journal: Cancer Discov Date: 2013-01-29 Impact factor: 39.397