Therapeutic targeting of RAS-driven cancers is one of the major unsolved challenges in human oncology. The primary goal of this proposal is to investigate the key events that cooperate with oncogenic RAS in thyroid transformation, and to understand how they modify tumor biology, cell signaling and response to therapies directed against RAS itself or its downstream effectors. Poorly differentiated (PDTC) and anaplastic thyroid cancers (ATC) are enriched for RAS mutations. We completed cancer gene exome sequencing of PDTC and ATC, which provide an unprecedented perspective of the ontogeny of RAS-mutant thyroid cancer. Two genes in particular, NF2 and EIF1AX, are strongly associated with RAS in thyroid cancer, and their functional impairment likely contributes to tumor progression. NF2 was not previously implicated in this disease and has not been studied in the context of mutant RAS. In the absence of merlin, the Hippo pathway is derepressed, leading to activation of a transcriptional complex engaged by YAP. Our discovery that RAS genes are themselves transcriptional targets of YAP-TEAD1 helps explain the augmentation of RAS signaling with merlin loss, and raises the possibility that other inputs into YAP may also contribute to thyroid tumorigenesis. This may have important ramifications for RAS-mutant cancers of other cell types. As for EIF1AX, the strong association with RAS in advanced disease was unexpected, since the two events were mutually exclusive in low grade thyroid cancers (PTC). Unraveling their functional interactions holds great potential for understanding tumor microevolution and response to therapy. Accordingly, we will pursue the following specific aims: 1. We will investigate mechanisms of mutant RAS cooperativity with NF2 loss in thyroid cancer. We will explore inputs into YAP from NF2 and other effectors, and determine which aspects of tumor promotion by NF2 loss are phenocopied by an activated mutant of YAP in the RAS context. We will also define the transcriptional partners of YAP-TEAD that contribute to RAS, as well as to global, gene regulation in thyroid cancer. 2. We will explore how EIF1AX mutants regulate translation and signaling in wild-type or RAS mutant cells, and determine the effect of combined defects of these two genes in mouse models. 3. We will define mechanisms of response and/or resistance to therapies targeting mutant HRAS or its effectors in cell lines and mouse models in the context of coexisting mutations of EIF1AX or of Nf2 deficiency.
We discovered that loss-of-function of NF2, the gene encoding for Merlin, and mutations of the translation initiation factor EIF1AX, are common events in poorly differentiated thyroid cancers, and are strongly associated with RAS mutations. We aim to understand how merlin cooperates with RAS to transform thyroid cells, based on evidence that this interaction is largely mediated by Hippo signaling to YAP, which enhances RAS gene expression and signaling and modulates responses to therapies targeting RAS itself or its downstream effectors. The functional consequences of the mutations of EIF1AX on translational regulation are unknown and will be studied as isolated events and in the context of RAS mutations.
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|Fagin, James A; Wells Jr, Samuel A (2016) Biologic and Clinical Perspectives on Thyroid Cancer. N Engl J Med 375:1054-67|
|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|
|Garcia-Rendueles, Maria E R; Ricarte-Filho, Julio C; Untch, Brian R et al. (2015) NF2 Loss Promotes Oncogenic RAS-Induced Thyroid Cancers via YAP-Dependent Transactivation of RAS Proteins and Sensitizes Them to MEK Inhibition. Cancer Discov 5:1178-93|
|Dunn, Lara; Fagin, James A (2015) Therapy: Lenvatinib and radioiodine-refractory thyroid cancers. Nat Rev Endocrinol 11:325-7|
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