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Dual inhibition of PI3K/mTOR signaling in chemoresistant AML primary cells
Jessika Bertacchini1, Chiara Frasson2, Francesca Chiarini3
1Cellular Signaling Unit, Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena 41125, Italy.
Abstract:
A main cause of treatment failure for AML patients is resistance to chemotherapy. Survival of AML cells may depend on mechanisms that elude conventional drugs action and/or on the presence of leukemia initiating cells at diagnosis, and their persistence after therapy. MDR1 gene is an ATP-dependent drug efflux pump known to be a risk factor for the emergence of resistance, when combined to unstable cytogenetic profile of AML patients. In the present study, we analyzed the sensitivity to conventional chemotherapeutic drugs of 26 samples of primary blasts collected from AML patients at diagnosis. Detection of cell viability and apoptosis allowed to identify two group of samples, one resistant and one sensitive to in vitro treatment. The cells were then analyzed for the presence and the activity of P-glycoprotein. A comparative analysis showed that resistant samples exhibited a high level of MDR1 mRNA as well as of P-glycoprotein content and activity. Moreover, they also displayed high PI3K signaling. Therefore, we checked whether the association with signaling inhibitors might resensitize resistant samples to chemo-drugs. The combination showed a very potent cytotoxic effect, possibly through down modulation of MDR1, which was maintained also when primary blasts were co-cultured with human stromal cells. Remarkably, dual PI3K/mTOR inactivation was cytotoxic also to leukemia initiating cells. All together, our findings indicate that signaling activation profiling associated to gene expression can be very useful to stratify patients and improve therapy.
Insights
Chemotherapy resistance in acute myeloid leukemia (AML) can be overcome by targeting MDR1 gene and PI3K signaling. Combining chemotherapy with signaling inhibitors shows potent cytotoxic effects, even on leukemia-initiating cells.
Area of Science:
- Hematology
- Molecular Biology
- Cancer Research
Background:
- Chemotherapy resistance is a primary cause of treatment failure in acute myeloid leukemia (AML).
- Mechanisms of resistance include drug efflux pumps like P-glycoprotein (encoded by the MDR1 gene) and the persistence of leukemia-initiating cells.
- High MDR1 gene expression and PI3K signaling are associated with poor outcomes in AML.
Purpose of the Study:
- To investigate the role of MDR1 gene expression, P-glycoprotein activity, and PI3K signaling in chemotherapy-resistant AML.
- To evaluate the efficacy of combining conventional chemotherapy with signaling inhibitors against resistant AML cells.
- To determine if this combination therapy can overcome resistance mediated by leukemia-initiating cells.
Main Methods:
- Analysis of drug sensitivity, cell viability, and apoptosis in 26 primary AML patient samples.
- Quantification of MDR1 mRNA levels, P-glycoprotein content, and activity.
- Assessment of PI3K signaling pathway activation.
- In vitro testing of combined chemotherapy and signaling inhibitors (PI3K/mTOR inhibitors) on AML cells, including co-culture with stromal cells.
Main Results:
- Resistant AML samples showed significantly higher MDR1 mRNA levels, P-glycoprotein activity, and PI3K signaling compared to sensitive samples.
- Combination therapy with signaling inhibitors demonstrated potent cytotoxic effects on resistant AML cells, reducing MDR1 expression.
- The combination therapy remained effective even when AML cells were co-cultured with human stromal cells.
- Dual PI3K/mTOR inactivation was cytotoxic to leukemia-initiating cells.
Conclusions:
- MDR1 gene expression and PI3K signaling are key contributors to chemotherapy resistance in AML.
- Targeting these pathways with combined therapy offers a promising strategy to resensitize resistant AML to chemotherapy.
- Signaling pathway profiling combined with gene expression analysis can aid in patient stratification and therapeutic improvement for AML.
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