Abstract LB190: Modulation of SPI1 transcriptional program contributes to the preclinical anti-tumor activity of SMARCA4/SMARCA2 ATPase inhibitors in AML

Abstract

Abstract SPI1 (PU.1) is an ETS family transcription factor that plays a critical role in hematopoietic development and differentiation. Regulation of SPI1 expression has also been implicated in Acute Myeloid Leukemia (AML) oncogenesis, though its mechanism is incompletely understood. Previously we have identified and characterized a series of novel dual inhibitors of the SMARCA4/SMARCA2 ATPases (also referred to as BRG1/BRM), critical components of the BAF (mSWI/SNF) family of chromatin remodeling complexes; and FHD-286, a related SMARCA4/SMARCA2 ATPase inhibitor, is currently being explored clinically for the treatment of metastatic uveal melanoma and AML (NCT04879017 and NCT04891757). Here we show that AML cell lines are sensitive to BAF ATPase inhibition, resulting in both cell cycle arrest and apoptosis. We demonstrate that BAF ATPase inhibition primarily affects the SPI1 transcriptional profile by regulating SPI1 genomic occupancy at various enhancer elements, resulting in downregulation of key target genes. Using in vivo mouse models of AML, we demonstrate dose-dependent tumor growth inhibition and pharmacodynamic modulation of SPI1 target genes. Together, these data suggest that modulation of SPI1 function may, in part, provide a mechanistic basis for the clinical development of FHD-286 in AML. Citation Format: Gabriel J. Sandoval, Katharine Feldman, Sal Topal, Ammar Adam, Hsin-Jung Wu, Darshan Sappal, Luis M. Soares, David L. Lahr, Lan Xu, Rishi G. Vaswani, Jordana Muwanguzi, Liyue Huang, Jessica Piel, Mike Collins, Ho Man Chan, Michael J. Thomenius, Steven F. Bellon, Ryan G. Kruger, Carl P. Decicco, Richard C. Centore, Martin Hentemann. Modulation of SPI1 transcriptional program contributes to the preclinical anti-tumor activity of SMARCA4/SMARCA2 ATPase inhibitors in AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB190.