Improved efficacy of quizartinib in combination therapy with PI3K inhibition in primary FLT3-ITD AML cells

Darici, Salihanur; Jørgensen, Heather G.; Huang, Xu; Serafin, Valentina; Antolini, Luciano; Barozzi, Patrizia; Luppi, Mario; Forghieri, Fabio; Marmiroli, Sandra; Zavatti, Manuela

doi:10.1016/j.jbior.2023.100974

Cited by 1 publication

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“…It has been proved that inhibiting multiple signaling pathways simultaneously can postpone the emergence of drug resistance to FLT3 inhibitors [60]. FLT3 inhibitors combined with PI3K inhibitors [61,62] displayed highly inhibit activity against FLT3-mutated AML. It is worth noticing that FLT3/CDK4/6 dual inhibitors, such as AMG 925 and FN-1501, recently developed to overcome the resistance by combining FLT3 and CDK4/6 inhibiting activities in one molecule [57,63].…”

Section: Strategies To Overcome Resistance To Flt3 Inhibitors In Amlmentioning

confidence: 99%

Strategies to overcome drug resistance in FLT3+ AML

Yang

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Acute myeloid leukemia (AML) is a hematopoietic malignancy with poor survival rate and limited therapeutic options. Targeted treatment of other types of cancer, for instance chronic myeloid leukemia (CML) and breast cancer, has seen significant progress. However, when it comes to AML, the outcome is poor with a five-year relative survival of only 20 - 30%. Over the last four years, the FDA has approved nine new drugs for AML patients in the United States. Unfortunately,the median overall survival of AML patients is still fairly low. For patients aged 70 years and older, the median overall survival is only about 10 months. Even for children with AML, the overall 5-year survival rate is 65 - 70%. A major cause of treatment failure is the development of treatment-induced drug resistance. The development of somatic mutations is one of the most common mechanisms of drug resistance. In AML, mutations in the FMS-like tyrosine kinase 3 (FLT3) gene are often present, with an incidence rate of ∼30% of cases. Most of these mutations are internal tandem duplications (ITD), present in approximately 25% of the patients.Patients with a high FLT3-ITD burden often relapse after chemotherapy. Inpatients with FLT3-ITD mutations, FLT3 has become a promising drug target for therapy. In the past few years, FLT3 inhibitors have led to clinical progress, but there are still some significant problems with their usage. Among these, drug resistance is urgent to overcome. This thesis mainly focuses on exploring different treatment regimens to over-come drug resistance in human FLT3+ AML cells as a model for the disease.Initially, a drug rotation protocol between two inhibitors which have different resistance profiles was tested. However, the results were not satisfying. Combi-nation therapy between a FLT3 inhibitor and another inhibitor was adopted. This strategy exhibited significant synergy and, more importantly, could postpone the emergence of drug resistance. In further experiments, we examined somenewly-developed small molecular compounds, and it turned out some of them had excellent inhibitory activity against established drug-resistant AML cell lines.In parallel, we have also studied the cause of resistance in these cells and have identified resistance mutations that have not been described before. Finally, we studied whether FLT3 inhibitors were likely to be synergistic with azacitidine, ahypomethylating agent approved for AML treatment. Such combinations did notdisplay a clear synergistic effect on AML cells, though one combination may be promising. Overall, our studies provided a better understanding of the resistance mechanisms by which FLT3-ITD cells overcome therapy and valuable information about the efficacy of novel inhibitors that are not currently in clinical use, and on combination therapies. To this end, the results will enable to further facilitate the rational development of new strategies to overcome drug resistance in FLT3+AML.

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Section: Strategies To Overcome Resistance To Flt3 Inhibitors In Amlmentioning

confidence: 99%

Strategies to overcome drug resistance in FLT3+ AML

Yang

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Improved efficacy of quizartinib in combination therapy with PI3K inhibition in primary FLT3-ITD AML cells

Cited by 1 publication

References 45 publications

Strategies to overcome drug resistance in FLT3+ AML

Strategies to overcome drug resistance in FLT3+ AML

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