Abstract 3068: CREBBP/EP300 disruption promotes tumor progression and confers synthetic lethality in anaplastic thyroid cancers

Abstract

Abstract Anaplastic thyroid cancers (ATC) are fast-growing, undifferentiated tumors and almost invariably fatal, primarily due to the lack of effective therapeutic options. The recent approval of dabrafenib plus trametinib for the treatment of BRAFV600E-mutant ATCs improved the prognosis of a subset of patients, but ineligibility and acquired resistance still limit their use. Overall, ATC patients remain in great need of tailored therapeutic options. We previously showed that loss-of-function alterations targeting histone acetyltransferase (HAT) genes, namely CREBBP and EP300, occur in 15-20% of ATCs, but only in <1% of their well-differentiated counterparts. What remains unknown are the specific mechanisms by which HAT disruptions perturb chromatin architecture, impact gene homeostasis, and unleash cellular processes in these aggressive tumors. We are assessing the HAT-mediated thyroid cancer progression. CREBBP/EP300 knockouts enhanced thyroid cancer cell proliferation in vitro and induced thyroid gland growth in a thyroid-specific mouse model of HAT loss. We are leveraging these animals to characterize the in vivo effects of Crebbp/Ep300 knockout, alone or in combination with BrafV600E, in thyroid cancer phenotypes and epigenetic reconfiguration. In addition, we are exploiting the molecular consequences of HAT loss to explore tailored treatments. CRISPR/Cas9 screens identified a mutual CREBBP/EP300-dependency of HAT-mutant human cancer cell models. Our experiments in thyroid cancer cells employing CREBBP/EP300-targeting proteolysis-targeting chimera (PROTAC) compounds specifically degraded these proteins and decreased histone acetylation. Our findings prove the oncogenicity of HAT loss in thyroid cancer progression and support exploring synthetic lethality dependencies in CREBBP/EP300-mutant ATCs. In summary, we provide pre-clinical basis to inform genomics-driven and mechanism-oriented decisions for the clinical management of patients with HAT-altered ATC. Citation Format: Jacob Haase, Talia A. Gebhard, Qi Liu, Sara G. Bernabé, Jingzhu Hao, Chisom Unegbu, Athanasios Bikas, Jun Qi, Iñigo Landa. CREBBP/EP300 disruption promotes tumor progression and confers synthetic lethality in anaplastic thyroid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3068.