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AML Microenvironment Catalyzes a Step-wise Evolution to Gilteritinib Resistance

Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. It is characterized by an aberrant proliferation of immature myeloblasts that infiltrate the bone marrow and impair normal hematopoiesis. AML is the most common type of acute leukemia in adults and usually worsens quickly if left untreated. An estimated 20,240 people in the United States will be diagnosed with AML and 11,400 will die from this disease in 2021.

Activating mutations in the FLT3 gene are the most common mutations in acute myeloid leukemia (AML). FLT3 mutations drive leukemia cell proliferation and are associated with higher rates of relapse and less favorable prognosis. Gilteritinib is a recently FDA-approved FLT3 inhibitor that is initially very efficacious in patients. However, despite effective inhibition of FLT3, residual cells survive in the marrow microenvironment and over time these early resistant cells evolve intrinsic resistance mechanisms to gilteritinib, or late resistance, thus limiting the durability of response.

In a newly published study in Cancer Cell by the National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (CPTAC), investigators used a comprehensive multiomics approach of proteomics, phospho-proteomics, whole exome sequencing, CRISPR screening, metabolomics, and small molecule screening to interrogate the evolution of early to late resistance in FLT3 mutated AML.

In investigating this evolution, the study showed that, although removing supportive ligands from the marrow microenvironment initially restored the cells’ sensitivity to gilteritnib, it also led to the expansion of NRAS mutations, which drove late resistance. However, interestingly, NRAS mutations were detectable at low levels in early resistance as well but did not provide a growth advantage in the presence of survival factors from the marrow microenvironment, and therefore, were not required in early resistance. Instead of relying on NRAS signaling for early resistance, the early resistant cells, which are dependent upon the marrow microenvironment, required aurora kinase B (AURKB) for growth, and exhibited slower cell cycle and alterations in metabolism.

With this new data, the study found that the combination of gilteritinib and an AURKB inhibitor (AZD2811) was very effective in early resistant leukemia cells, suggesting a novel clinical strategy to target residual leukemia cells prior to the expansion of intrinsic resistance NRAS mutations. Exploiting this unique vulnerability of early resistance may, therefore, thwart multiple mechanisms of late resistance and improve the durability of response to gilteritinib for patients with AML.

Source: The AML microenvironment catalyzes a step-wise evolution to gilteritinib resistance. Cancer Cell, 2021 June 24 DOI: https://doi.org/10.1016/j.ccell.2021.06.003