AUTX703, a Novel and Potent KAT2A and KAT2B Protein Degrader, Induces Differentiation and Offers Survival Advantage in a Primary Human AML Xenograft Model
Abstract
Phenotypic plasticity, or the ability of cancer cells to switch between cell states, has recently been recognized as a key hallmark of cancer. Cancer cells can hijack normal developmental pathways, preventing terminal differentiation which pushes cells to a more proliferative, plastic cell state similar to those found in early development. To identify therapeutic targets driving tumor plasticity, we utilized our proprietary AI/ML platform to create a high-resolution atlas of normal human development. Tumors were mapped to the atlas using our CLASSIFY algorithm to define their altered cell state and our DRIVE algorithm was used to identify the genes driving the oncogenic cell state. Our platform identified KAT2A, a lysine acetyltransferase, as a key driver in AML.
KAT2A and its paralog lysine acetyltransferase 2B (KAT2B) are epigenetic enzymes involved in normal human development and have been shown to play a critical role in regulating somatic cell fate decisions. Histone acetylation can activate transcriptional programs necessary to drive cell fate. KAT2A expression has been shown to homogenize transcriptional programs to sustain stem cell phenotypes, while loss of KAT2A has been shown to promote differentiation.
Genetic validation of KAT2A as a therapeutic target was performed in the AML cell line, MOLM-13, where knockdown resulted in significant cell growth inhibition and induction of cell state changes consistent with a more mature differentiated phenotype. Following…
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