Abstract CN07-04: Maximizing the effectiveness of radioiodine therapy for metastatic thyroid cancer with selective inhibitors of MAPK signaling.
Authors: Fagin James A. 
Published: August 2014

Abstract
Thyroid cancers are associated with mutually exclusive point mutations of BRAF (57%) and RAS (NRAS &gt;HRAS; 12%), and fusion events activating BRAF, or the RTKs RET, NTRK1 or NTRK3. The molecular taxonomy of the disease is different in more advanced forms of thyroid cancer. Although BRAF mutations also predominate, poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC) are relatively enriched for RAS mutations (23-44%). As predicted from the genetics of the disease, thyroid cancers, like melanomas, are ERK-driven tumors. However, they exhibit lineage-specific properties that offer distinct therapeutic opportunities and challenges. The 10-year survival of patients with metastatic thyroid cancers that retain radioiodine (RAI) avidity is ∼60%, whereas it is only 10% if the metastases are refractory to RAI therapy (1). There are several lines of evidence indicating that constitutive MAPK activity causes decreased radioiodine responsiveness. Conditional expression of oncogenic RET/PTC, RAS or BRAF in thyroid PCCL3 cells downregulates expression of the sodium iodide symporter (NIS) and other key genes required to organify and retain iodide (2, 3), which is restored by treatment with RAF or MEK inhibitors (2, 4). Mice with dox-inducible expression of BRAFV600E in thyroid cells develop invasive papillary thyroid cancers with profoundly impaired expression of genes required for iodine uptake and metabolism and of 124-iodine uptake in vivo, which are reversed when dox is discontinued, but only partially restored by RAF or MEK inhibitors (5). Based on these findings we performed a phase 2 trial of the MEK inhibitor selumetinib (AZD6244) in patients with RAI-refractory thyroid cancer. Selumetinib increased iodide incorporation at metastatic sites in 12/20 patients as determined by 124I PET scanning, and in ∼40% (8/20) the increase in uptake was sufficient to enable treatment with 131I, with remarkable clinical responses (6). Responses were greater in patients whose tumors harbored RAS as compared to BRAF mutations. An international multicenter phase 3 registration study of selumetinib vs placebo to increase remission rates of high risk thyroid cancer patients receiving post-surgical adjuvant radioiodine therapy is now in progress (the ASTRA trial).
There is concern that responses to monotherapy with MEK or RAF inhibitors may not be optimal, particularly in BRAF-mutant disease. We find that BRAF-mutant human thyroid cancer cell lines have decreased responsiveness to RAF and MEK inhibitors because of relief of negative feedback resulting in derepression of HER3 transcription, followed by neuregulin-1- induced HER3/HER2 signaling and reactivation of the MEK-ERK and PI3K-AKT pathways, which is overcome by co-treatment with HER kinase inhibitors (7). This mechanism of adaptive resistance differs in significant ways from the responses seen in BRAF-mutant melanoma and colorectal cell lines.
Our preclinical data predicts that optimal restoration of RAI responsiveness would be best achieved by compounds that inhibit MAPK output in a profound and sustained way. Indeed, recent experiments show that such strategies have excellent potential to further augment the specialized functions of thyroid cells, and lead to even more effective therapies.
Citation Information: Mol Cancer Ther 2013;12(11 Suppl):CN07-04.
Citation Format: James A. Fagin. Maximizing the effectiveness of radioiodine therapy for metastatic thyroid cancer with selective inhibitors of MAPK signaling. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr CN07-04.