Exploring Mechanisms of Action in Combinatorial Therapies through Solubility Alterations: Advancing AML Treatment

Abstract

Acute myeloid leukemia (AML) is an aggressive blood cancer with a poor prognosis. Although treatments like allogeneic hematopoietic stem cell transplantation and high-dose chemotherapy can potentially cure some younger patients, challenges such as relapse and treatment-related toxicities remain significant. Combination therapy has been a cornerstone in AML treatment, offering enhanced efficacy by leveraging the synergistic effects of multiple agents. However, high toxicity levels and the genetic heterogeneity of AML complicate the identification of effective and universally applicable drug regimens. To address these challenges, we introduce Co-PISA (Combination-Proteome Integral Stability Analysis), an innovative method designed to study drug-target interactions specifically within combination therapies. Co-PISA detects changes in protein stability that occur only when two drugs are used together, revealing cooperative mechanisms that single-drug treatments cannot achieve. We applied this method to two highly effective and low-toxicity drug combinations in AML, previously introduced in our group: LY3009120-Sapanisertib (LS) and Ruxolitinib-Ulixertinib (RU). Co-PISA utilizes advanced proteomic tools to investigate both primary and secondary target effects, providing a deeper understanding of how combination therapies influence multiple signaling pathways to overcome resistance. Furthermore, we propose a novel concept termed "conjunctional inhibition", where the combined action of drugs induces biological responses that cannot be replicated by individual agents. This approach shifts the paradigm in drug development and offers new directions for more effective treatments in AML and other complex diseases.