Overcoming BRAF/MEK Inhibition Resistance in Anaplastic Thyroid Carcinoma

ASPIRE Award (2020-Present)

Jennifer Wang, MD (Principal); Mark Zafereo, MD; and Wenyi Wang, PhD, The University of Texas MD Anderson Cancer Center

Jennifer Wang, MD

Mark Zafereo, MD

Wenyi Wang, PhD

Anaplastic thyroid carcinoma (ATC) is a rare and lethal form of cancer that has a very poor prognosis with over 80% of patients succumbing to their disease within 1 year of diagnosis. About 50% of patients have tumors with a common mutation in the BRAF protein called BRAF V600E. Patients whose tumor contain the V600E mutation experience better survival rates when treated with DT therapy,  a combination of two drugs, dabrafenib, which targets BRAF, and trametinib, which targets downstream cellular signaling pathway protein MEK. DT treatment leads to a reduction in tumor burden that improves successful surgical resection of residual tumor after treatment. Unfortunately, ATC tumors frequently develop resistance to this treatment, and patients frequently relapse.

Jennifer Wang, Wenyi Wang, and Mark Zafereo seek to understand the underlying mechanisms for ATC tumor resistance to DT. They hypothesize tumor heterogeneity, the genetic differences across the cells comprising a tumor, may facilitate resistance. They also believe factors in the tumor immune microenvironment could impact disease progression. To explore the role of these tumor characteristics further, they are collecting and analyzing a comprehensive set of BRAF V600E ATC tumor samples obtained before and after tumor resection from patients treated with either DT or DT plus the PD-1 targeting checkpoint inhibitor pembrolizumab. They will collect extensive genomic data along with histopathology with the aim of uncovering insights that will lead to improved assessment of a patient’s risk for disease progression and chart a path for better therapeutic strategies that could increase overall survival.

Published Research

Cao S, Wang JR, Ji S, Yang P, Dai Y, Guo S, Montierth MD, Shen JP, Zhao X, Chen J, Lee JJ, Guerrero PA, Spetsieris N, Engedal N, Taavitsainen S, Yu K, Livingstone J, Bhandari V, Hubert SM, Daw NC, Futreal PA, Efstathiou E, Lim B, Viale A, Zhang J, Nykter M, Czerniak BA, Brown PH, Swanton C, Msaouel P, Maitra A, Kopetz S, Campbell P, Speed TP, Boutros PC, Zhu H, Urbanucci A, Demeulemeester J, Van Loo P, Wang W. Estimation of tumor cell total mRNA expression in 15 cancer types predicts disease progression. Nat Biotechnol. 2022.

Wang JR, Montierth M, Xu L, Goswami M, Zhao X, Cote G, Wang W, Iyer P, Dadu R, Busaidy NL, Lai SY, Gross ND, Ferrarotto R, Lu C, Gunn GB, Williams MD, Routbort M, Zafereo ME, Cabanillas ME. Impact of Somatic Mutations on Survival Outcomes in Patients With Anaplastic Thyroid Carcinoma. JCO Precis Oncol. 2022.

Chen YH, Cabanillas M, Sperling J, Xu L, Goswami M, Maniakas A, Williams MD, Lai SY, Busaidy N, Dadu R, Zafereo ME, Wang JR. Prior thyroid and non-thyroid cancer history do not significantly alter overall survival in patients diagnosed with anaplastic thyroid carcinoma. Thyroid. 2022.

Zhao X, Wang JR, Dadu R, Busaidy N, Xu L, Learned K, Chasen NN, Vu T, Maniakas A, Eguia A, Diersing J, Gross ND, Goepfert RP, Lai SY, Hofmann MC, Ferrarotto R, Lu C, Gunn B, Spiotto M, Subbiah V, Williams MD, Cabanillas M, Zafereo ME. Surgery after BRAF-directed therapy is associated with improved survival in BRAF V600E mutant Anaplastic Thyroid Cancer. Thyroid. 2023.

Chen YH, Cabanillas M, Sperling J, Xu L, Goswami M, Maniakas A, Williams MD, Lai SY, Busaidy N, Dadu R, Zafereo ME, Wang JR. Prior Thyroid and Nonthyroid Cancer History Do Not Significantly Alter Overall Survival in Patients Diagnosed with Anaplastic Thyroid Cancer. Thyroid. 2023.

Lu L, Wang JR, Henderson YC, Bai S, Yang J, Hu M, Shiau CK, Pan T, Yan Y, Tran TM, Li J, Kieser R, Zhao X, Wang J, Nurieva R, Williams MD, Cabanillas ME, Dadu R, Busaidy NL, Zafereo M, Navin N, Lai SY, Gao R. Anaplastic transformation in thyroid cancer revealed by single-cell transcriptomics. J Clin Invest. 2023.

Wang JR, Zafereo ME, Wang W, Joshu C, Ray D. Association of Polygenic Score With Tumor Molecular Subtypes in Papillary Thyroid Carcinoma. J Clin Endocrinol Metab. 2023.