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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Yassin, Rihab R,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Sloan-Kettering Institute for Cancer Research
New York
United States
Zip Code
Goodwin, Alice F; Tidyman, William E; Jheon, Andrew H et al. (2014) Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation. Hum Mol Genet 23:682-92
Malaguarnera, Roberta; Chen, Kuen-Yuan; Kim, Tae-Yong et al. (2014) Switch in signaling control of mTORC1 activity after oncoprotein expression in thyroid cancer cell lines. J Clin Endocrinol Metab 99:E1976-87
Landa, Inigo; Ganly, Ian; Chan, Timothy A et al. (2013) Frequent somatic TERT promoter mutations in thyroid cancer: higher prevalence in advanced forms of the disease. J Clin Endocrinol Metab 98:E1562-6
Ryder, Mabel; Gild, Matti; Hohl, Tobias M et al. (2013) Genetic and pharmacological targeting of CSF-1/CSF-1R inhibits tumor-associated macrophages and impairs BRAF-induced thyroid cancer progression. PLoS One 8:e54302
Xing, Mingzhao; Alzahrani, Ali S; Carson, Kathryn A et al. (2013) Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA 309:1493-501
Ho, Alan L; Grewal, Ravinder K; Leboeuf, Rebecca et al. (2013) Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 368:623-32
Montero-Conde, Cristina; Ruiz-Llorente, Sergio; Dominguez, Jose M et al. (2013) Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas. Cancer Discov 3:520-33
Gild, Matti L; Landa, Inigo; Ryder, Mabel et al. (2013) Targeting mTOR in RET mutant medullary and differentiated thyroid cancer cells. Endocr Relat Cancer 20:659-67
Ricarte-Filho, Julio C; Matsuse, Michiko; Lau, Christopher et al. (2012) Absence of common activating mutations of the epidermal growth factor receptor gene in thyroid cancers from American and Japanese patients. Int J Cancer 130:2215-7; author reply 2217-8
Knauf, J A; Sartor, M A; Medvedovic, M et al. (2011) Progression of BRAF-induced thyroid cancer is associated with epithelial-mesenchymal transition requiring concomitant MAP kinase and TGFýý signaling. Oncogene 30:3153-62

Showing the most recent 10 out of 14 publications