The gain-of-function BRAFT1799A mutation is highly prevalent in melanomas and in thyroid cancers. In the latter, BRAF mutations confer poor prognosis. The spectacular early results of clinical trials in patients with metastatic melanoma treated with the selective RAF inhibitor PLX4032 serve as yet another proof that advanced cancers often retain dependency on oncogenic kinases activated in early stages of tumorigenesis. However, response to selective kinase inhibition is not uniform between tumors of different lineages harboring the same mutation (e.g. in BRAF). The mechanisms that account for this are unknown. Data generated during this granting cycle point to important differences in the biology of thyroid cancers initiated by oncogenic BRAF as compared to melanomas, as well as in the response of murine thyroid cancers and human cell lines to MEK and RAF inhibitors. The experiments proposed in this application aim to explore the key determinants of this differential response, and whether thyroid cancers can be sensitized to MAPK inhibition by selectively targeting feedback events that arise after perturbation of the network. For this we will: 1. Examine mechanisms of primary resistance to RAF and MEK inhibitors, and of feedback reactivation of RTK signaling in thyroid cancer cell lines. 2. Identify the profile of RTK activation after acute exposure to MEK or RAF inhibitors in vivo, and determine the effects of suppressing their activity. 3. Explore mechanisms of acquired resistance to the selective RAF inhibitors in BRAF (+) thyroid cancer cell lines, murine thyroid cancers, and in metastatic lesions of BRAF (+) thyroid cancer patients treated with PLX4032.
This proposal will investigate why thyroid cancers appear to be comparatively resistant to targeted drugs that block the activity of the cancer protein encoded by the BRAF oncogene, which is a common cause of the disease. We have discovered that after thyroid cancer cells or mice with thyroid cancer are treated with BRAF antagonists, they respond by turning on the activity of certain growth factor receptors, which allows them to continue to grow. By exploring how these cancers become resistant to the RAF inhibitors, we believe we can block the resistance mechanisms and obtain better responses to these promising targeted therapies.
|Bellelli, Roberto; Vitagliano, Donata; Federico, Giorgia et al. (2018) Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia. Mol Cell Endocrinol 460:24-35|
|Krishnamoorthy, Gnana P; Davidson, Natalie R; Leach, Steven D et al. (2018) EIF1AX and RAS mutations cooperate to drive thyroid tumorigenesis through ATF4 and c-MYC. Cancer Discov :|
|Untch, Brian R; Dos Anjos, Vanessa; Garcia-Rendueles, Maria E R et al. (2018) Tipifarnib Inhibits HRAS-Driven Dedifferentiated Thyroid Cancers. Cancer Res 78:4642-4657|
|Azouzi, Naïma; Cailloux, Jérémy; Cazarin, Juliana M et al. (2017) NADPH Oxidase NOX4 Is a Critical Mediator of BRAFV600E-Induced Downregulation of the Sodium/Iodide Symporter in Papillary Thyroid Carcinomas. Antioxid Redox Signal 26:864-877|
|Ibrahimpasic, Tihana; Xu, Bin; Landa, Iñigo et al. (2017) Genomic Alterations in Fatal Forms of Non-Anaplastic Thyroid Cancer: Identification of MED12 and RBM10 as Novel Thyroid Cancer Genes Associated with Tumor Virulence. Clin Cancer Res 23:5970-5980|
|Montero-Conde, Cristina; Leandro-Garcia, Luis J; Chen, Xu et al. (2017) Transposon mutagenesis identifies chromatin modifiers cooperating with Ras in thyroid tumorigenesis and detects ATXN7 as a cancer gene. Proc Natl Acad Sci U S A 114:E4951-E4960|
|Landa, Iñigo; Ibrahimpasic, Tihana; Boucai, Laura et al. (2016) Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 126:1052-66|
|Nagarajah, James; Le, Mina; Knauf, Jeffrey A et al. (2016) Sustained ERK inhibition maximizes responses of BrafV600E thyroid cancers to radioiodine. J Clin Invest 126:4119-4124|
|Fagin, James A; Wells Jr, Samuel A (2016) Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med 375:1054-67|
|Dogan, Snjezana; Wang, Lu; Ptashkin, Ryan N et al. (2016) Mammary analog secretory carcinoma of the thyroid gland: A primary thyroid adenocarcinoma harboring ETV6-NTRK3 fusion. Mod Pathol 29:985-95|
Showing the most recent 10 out of 42 publications