Poorly differentiated thyroid cancer (PDTC) is a very aggressive and invasive neoplasm that arises from the thyroid follicular cells and is characterized by a poor prognosis due to its resistance to current therapeutic modalities, including radioiodine and chemotherapy. Therefore, targeted therapy for this type of cancer is an area of high interest and several kinase inhibitors are currently in clinical trials. However, these inhibitors present certain limitations due to intrinsic or acquired drug resistance. Thus, targeted therapy using drug combinations to increase efficiency and prevent resistance is an attractive strategy. However, one major obstacle to our understanding of the molecular mechanisms leading to tumor aggressiveness and drug resistance in PDTCs has been the relative rarity of this disease and the absence of relevant mouse models. By simultaneously activating Kras and deleting p53 in thyroid follicular cells, we have generated a novel mouse model that develops papillary thyroid cancer invariably progressing to PDTC. These tumors are morphologically and functionally similar to their human counterparts and depend on MEK/ERK signaling for proliferation. Driver pathway inhibition in primary mouse carcinomas as well as carcinoma-derived cells, using the FDA approved MEK inhibitor, Trametinib, shows that these tumors are intrinsically resistant to cell death, due at least in part to their high levels of expression of the anti-apoptotic Bcl2 family members Bcl2a1 and Mcl1. Similar overexpression of anti-apoptotic molecules is observed in a large subset of human thyroid carcinomas. Our in vitro and in vivo studies show that Obatoclax, a small molecule pan inhibitor of the anti-apoptotic Bcl2 family members, induces cell death in mouse PDTC cell lines as well as in human thyroid cancer cells. This effect is even greater when combining Obatoclax with Trematinib. Furthermore, Obatoclax also synergizes with chemotherapeutic drugs such as doxorubicin and paclitaxel, currently used in the treatment of thyroid cancer. Therefore, our study, using a new PDTC mouse model as well as human thyroid cancer cell lines, shows that overexpression of anti-apoptotic Bcl2 family members marks aggressive thyroid carcinomas which can be targeted by inhibitors such as Obatoclax, alone or in combination with other therapeutic approaches. These data support the development of novel effective treatment options for aggressive thyroid carcinomas, which can be rapidly translated to the clinical setting.

Citation Format: Devora Champa, Ronald Ghossein, Antonio Di Cristofano. Aggressive thyroid carcinomas are intrinsically resistant to apoptosis but can be effectively targeted by a Bcl2 family inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2755. doi:10.1158/1538-7445.AM2014-2755