Abstract 7013: RGT-61159, best-in-class oral small molecule inhibitor of MYB via selective RNASplicing alteration, synergistic anti-tumor aActivity when combined with standards of care in leukemia disease models harboring AML common genetic lesions and with NOTCH inhibitors in ACC disease models
Authors: Norman Lu, Patricia Soulard, Xiubin Gu, Chris Yates, Kai Li, Sam Hasson, Ibrahim Kay, Zhiping Weng, Travis Wager, Simon Xi
Journal: Cancer Research (2025)

Abstract The oncogenic transcription factor MYB is a master regulator of self-renewal, differentiation and proliferation of hematopoietic cells. MYB is frequently aberrantly expressed in hematologic malignancies and has been revealed to be a central component of oncogenic complexes maintaining aberrant gene expression programs in AML. RGT-61159 is a potent, selective oral small molecule inhibitor of the oncogene MYB via the inclusions of a cryptic exon into MYB RNA transcripts, resulting in the activation of the nonsense-mediated decay pathway promoting MYB mRNA depletion and sequentially MYB protein degradation. The RGT-61159 Phase 1 study in adults with relapsed/​refractory ACC or CRC has been initiated (NCT06462183). Here, we report genomic analyses of different AML cell lines treated with RGT-61159 that provided further insight into key oncogenes (e.g., BCl2, NOTCH, MYC) directly regulated by MYB. To further evaluate RGT-61159’s potential to treat leukemia, RGT-61159 single agent was profiled in a battery of murine models of AML harboring the most common genetic lesions (e.g., Flt3 ITD, MLL-fusion and NPM1 mutation). RGT-61159 showed significant anti-tumor activity across the different AML tumor models tested along with robust MYB RNA depletion in tumor cells at tolerated doses. In addition, the benefit of combining RGT-61159 with a panel of standard-of-care agents for AML treatment was explored in vitro across a panel of AML cell lines harboring different genetic alterations. The data revealed synergistic cell killing activity when RGT-61159 was combined with Flt3 inhibitors (e.g. gilteritinib and midostaurin) in MOLM-13 and MV4.11 cell lines harboring Flt3 IDT mutation, and with menin inhibitors (e.g. KO-539, revemenib) in AML cell lines with NPM1 mutant) or MLL-fusion. Finally, RGT-61159 combination with a Bcl2 inhibitor (venetoclax) resulted in synergistic cell killing activity in AML cell lines carrying NPM1 mutations or AML-1-ETO fusion protein. These studies provide compelling supportive evidence for combining RGT-61159 with standards-of-care for AML treatment in the relevant population of patients with AML. . Citation Format: Norman Lu, Patricia Soulard, Xiubin Gu, Chris Yates, Kai Li, Sam Hasson, Ibrahim Kay, Zhiping Weng, Travis Wager, Simon Xi. RGT-61159, best-in-class oral small molecule inhibitor of MYB via selective RNASplicing alteration, synergistic anti-tumor aActivity when combined with standards of care in leukemia disease models harboring AML common genetic lesions and with NOTCH inhibitors in ACC disease models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7013.