Abstract 5192: MYC amplification and overexpression Is associated With metastasis and drug resistance in a mouse model of anaplastic thyroid carcinoma.

Abstract

Abstract Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to every therapeutic approach. We have generated a mouse model in which simultaneous selective activation of the PI3K pathway and inactivation of p53 in thyroid epithelial cells leads to the development of ATC. These tumors display all the typical features of their human counterpart and metastasize to the lungs in over 25% of cases (20 out of 76). Recent data have indicated that mammary tumors driven by PI3K activation quickly become resistant to PI3K inhibitors through mechanisms that include Myc amplification. We have used our model to test the hypothesis that Myc overexpression and/or amplification might contribute the aggressive features of PI3K-driven ATC. Analysis of 46 primary tumors developed by [Pten,p53]thyr-/− mice using a high-sensitivity real-time PCR approach demonstrates that the Myc locus is amplified (copy number ≥4) in about 25% of cases. Conversely, none of 20 metastatic follicular thyroid carcinomas developed by Ptenthyr-/− mice displayed Myc amplification. More strikingly, Myc is amplified in almost 50% (7/15) of ATCs with distant metastases, suggesting that Myc amplification confers more aggressive features to PI3K-driven anaplastic tumors, even in the absence of drug mediated selective pressure. Furthermore, when injected in syngeneic mice, cell lines established from Myc-amplified tumors grow faster than cell lines derived from tumors without Myc amplification. Myc-amplified cell lines are more resistant than Myc-diploid cells to the PI3K inhibitor BKM120, as well as to paclitaxel and doxorubicin treatment, and this increased resistance can be abrogated by shRNA-mediated Myc downregulation. These data support a model in which Myc cooperates with PI3K activation to induce more aggressive features, including drug resistance and enhanced metastatic behavior, in advanced thyroid carcinomas. Furthermore, these data lay the basis for new studies aimed at increasing therapeutic efficacy by interfering with Myc and Myc-dependent pathways. Citation Format: Marika A. Russo, Antonio Di Cristofano. MYC amplification and overexpression Is associated With metastasis and drug resistance in a mouse model of anaplastic thyroid carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5192. doi:10.1158/1538-7445.AM2013-5192