Abstract LB198: CETSA-driven targeted proteomics for personalized AML therapies: Investigating drug response biomarkers and resistance mechanisms

Abstract Cancer drug resistance remains a critical challenge in cancer therapy, necessitating advanced approaches to understand and counteract this phenomenon. Acute myeloid leukemia (AML), an aggressive and heterogeneous cancer, often exhibits resistance to chemotherapy, contributing to high relapse rates. We are employing a Cellular Thermal Shift Assay (CETSA)-driven targeted proteomics workflow to investigate drug response biomarkers and resistance mechanisms, with the ultimate goal of enabling personalized AML therapies. In our previous publication (Ramos et al., 2024) we identified several biomarkers induced by different cancer drugs. CETSA allows for the direct assessment of a diverse range of biochemical effects in cells, providing crucial insights into drug-induced biomarker responses. Initial results from our study reveal distinct CETSA differences between drug treatments and inter-patient variability in CETSA biomarkers, even for the same treatment. For example, while some patients show a robust response to venetoclax, others exhibit limited biomarker changes. Limited biomarker response to venetoclax and no detectable CETSA apoptosis biomarker response to azacitidine were observed in one patient, with azacitidine-specific changes, suggesting potential resistance downstream of these markers. Additionally, some patients appear highly responsive to venetoclax but not to azacitidine, with no additive effect observed when the two drugs are combined. These findings underscore the variability in therapeutic response across patients and emphasize the need for personalized approaches in AML management. By quantifying protein stability levels following treatment with apoptosis-inducing drugs, this targeted approach confirms the relevance of previously identified biomarkers and supports their role in predicting therapeutic efficacy. Although we do not yet have data from relapsed patients, obtaining such samples is a key goal for the future. These data will allow us to evaluate whether initial treatment responses align with relapse outcomes and may provide critical insights into resistance mechanisms. Understanding CETSA proteomic changes in relapsed patients could uncover key biochemical shifts associated with treatment resistance, ultimately guiding the development of more effective and personalized therapeutic strategies. While this study is ongoing and not yet influencing clinical practice, the emerging data supports the potential for application of CETSA in personalized biomarker-driven cancer therapy. By measuring CETSA-derived biomarkers with targeted proteomics, we aim to lay the foundation for real-time, precision-guided treatment in AML. Furthermore, these insights may extend to other cancer types, advancing the broader goal of personalized oncology. - Ramos et al. Proteome-wide CETSA reveals diverse apoptosis-inducing mechanisms converging on an initial apoptosis effector stage focused at the peripheral region of the nucleus. Cell Reports, 2;43(10):114784. Citation Format: Anderson Daniel Ramos, Smaranda Bacanu, Sara Lööf, Sofia Bengtzén, Jiawen Lyu, Sören Lehmann, Pär Nordlund. CETSA-driven targeted proteomics for personalized AML therapies: Investigating drug response biomarkers and resistance mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB198.