Abstract P092: A novel approach to target drug-resistance in thyroid cancer by regulating Annexin 7 (ANXA7)/p21 axis

Thyroid cancer is the most common endocrine malignancy in the United States. The survival rate of thyroid cancer patients is high. However, there is a group of patients with poor prognosis due to the development of drug resistance. Differential expression and mutation of the BRAF, Met, and p53 genes have been correlated with the progression and aggressiveness of this cancer, and over 60% of thyroid cancer patients were found to have a V600E mutation in BRAF. ANXA7 is a multifunctional protein that has been found to act as a tumor suppressor in many cancers. In this study, we focused on the expression of ANXA7 in relation to the BRAF mutation and its functional role in regulating thyroid cancer progression, aggressiveness, and drug-sensitivity. High-throughput RNA-seq and protein array studies indicated a lower ANXA7 protein expression linked with thyroid cancer. Additionally, ANXA7 was found to be lower in the thyroid cancer cell lines with the BRAF mutation. To test ANXA7’s role in regulating drug-sensitivity, thyroid cancer cells were treated with different BRAF and MEK inhibitors. Both groups of inhibitor treatment on the thyroid cancer cells resulted in an increase in ANXA7 expression, a decrease in Ph-ERK, and an increase in apoptotic markers. We also found that the cyclin-dependent kinase inhibitor p21 is a novel regulator of BRAF mediated chemoresistance, and elevation of both p21 and ANXA7 through the combination of drugs resulted in a synergistic effect in the apoptotic pathway. Together, these results provide new insights into thyroid malignancy and its drug resistance mechanism involving the ANXA7/p21/BRAF/MAPK pathway. Future translational-based approaches with high-throughput functional screenings are necessary to develop a novel and effective ANXA7-based therapeutic strategy for thyroid cancer. Citation Format: Surya Radhakrishnan, Alakesh Bera, Narayanan Puthillathu, Nahbuma Gana, Madhan Subramanian, Eric Russ, Anubhuti Paria, Swarnarup Paria, Stephen Rothwell, Harvey B. Pollard, Meera Srivastava. A novel approach to target drug-resistance in thyroid cancer by regulating Annexin 7 (ANXA7)/p21 axis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P092.