Rational p300/CREBBP KAT inhibition in AML

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Acute myeloid leukemias (AML) are aggressive blood cancers with a dismal prognosis of only 30% survival rate at 5 years. AML possess an extraordinary capacity to evolve continuously and adapt under treatment. This characteristic is critically controlled through adjustments of epigenetic processes. Along the fact that epigenetic regulators are commonly mutated in AML, this property designates drugs targeting epigenetic modifications as suitable therapies for such cancers. However, clinical trials with single compounds targeting epigenetic modifiers have often disappointed due to either a primary lack of response, or the subsequent acquisition of non-genetic (mechanistic) adaptation. With this project, I intend to avoid a similar outcome for a currently emerging class of epigenetic modulators – p300/CREBBP lysine acetyltransferase (KAT) inhibitors. To do so, we will initially perform a comprehensive mechanistic and functional deconstruction of the p300/CREBBP roles in diverse models of AML, and then conduct an integrative assessment of the effects of p300/CREBBP KAT inhibition in both treatment-naïve and -resistant settings. Methodologically, we will use a series of up-to-date epigenomic, proteomic and functional techniques in multiple orthogonal systems (cell lines, primary human samples and murine models). This integrative approach will show AML type-specific dynamics at chromatin during treatment response and development of resistance, while also minimizing experimental biases. The necessity of such a complex mechanistic deconstruction is emphasized in our preliminary results. These show a previously unanticipated repressive function of p300/CREBBP to counteract a cell-death inducing interferon response in 50% of all tested AMLs. This is surprising, because p300/CREBBP have mostly been studied in AML for their chromatin-activating functions. We show in our preliminary data that the reliance on p300/CREBBP can be enhanced synthetically, for example through chronic inhibition of bromodomain and extraterminal (BET) proteins. We also show that non-genetic resistance to p300/CREBBP inhibitors causes higher dependency on other druggable epigenetic modulators, such as the canonical chromatin remodeling BAF complex. I propose to exploit these insights (and also results that we will obtain in our first parts of this project) by including p300/CREBBP KAT inhibitors in a rational sequential treatment strategy with 3-4 epigenetic inhibitors, and thus guide treatment trajectories in AML by gradually decreasing plasticity. I hypothesize that this project will critically influence the successful clinical implementation of p300/CREBBP KAT inhibitors to treat AML and will further serve as an example for other next-generation epigenetic modulators.