Saladi, Srinivas Vino V; Garg, Swati; Weisberg, Ellen L; Case, Abigail E; Ni, Wei; Pareek, Siddhika; Podar, Klaus; Salgia, Ravi; Griffin, James D; Stone, Richard M; Sattler, Martin
description
Acute myeloid leukemia (AML) is characterized by poor survival, especially in older patients with relapse/refractory disease. With an apparent lack of reliable long-term treatments, pathways involved in chromatin regulation represent potentially leverageable targets. The arginine methyltransferase CARM1 is a known dependency in AML, yet clinical grade inhibitors have remained elusive. We found that CARM1 promotes DNA repair and other pathways associated with malignant growth. Dysregulation of DNA repair pathways is pervasive in AML and linked to the transforming phenotype. Interestingly, targeting CARM1 chemosensitized AML cells for DNA-PK inhibition by peposertib, thereby blocking NHEJ (non-homologous end joining). Also, H3K27ac (histone H3 lysine 27 acetylation) active enhancer marks and marks of the corresponding histone acetyltransferase, P300, were found at the promoter region of relevant CARM1-regulated DNA repair enzymes. Consequently, our results show that CARM1 dependencies could also be exploited by utilizing inobrodib, a p300/CBP bromodomain inhibitor that synergizes with peposertib treatment in AML cells. Overall, these data demonstrate a rational approach for combination therapy by exploiting dependencies through inhibition of proximal effector function in addition to essential NHEJ repair, targeting its rate-limiting enzyme complex, thereby resulting in synergistic inhibition in primary AML.
