biostudies-literatureUnknownGarciaz SAmidexAcute myeloid leukaemia (AML) is a severe disease occurring mainly in the elderly population. Venetoclax (VEN) combined with azacitidine has changed the paradigm of treatment of AML. Nevertheless, approximately 30% of patients are primary refractory to VEN (VEN-R), with no current therapeutic option. To target VEN-R AML, we collected primary blasts at AML diagnosis in a prospective biobanking trial (NCT02320656). We performed targeted Next Generation Sequencing and ex vivo drug testing in 108 AML samples. We noticed that 17 (15.7%) were navitoclax-resistant (NAV-R). We observed a strong anticorrelation between NAV and Dasatinib (DASA) ex vivo sensitivity, also found in the BEAT-AML cohort. As NAV and ABT797 are both BCL2/BCLxL inhibitors, we hypothesized that blasts sensitive to DASA (DASA-S) were dependent on MCL1. We performed BH3 profiling in 25 samples confirming MCL1 dependency. Immunoblots showed a higher MCL1 and BIM protein expression. We found a dose-dependent decrease in MCL1 protein expression associated with caspase 3 activation upon DASA in a primary AML sample. Collectively, these results suggest that DASA degrades MCL1 and effectively kills AML cells. To prove this hypothesis, we designed a phase II clinical trial named VEN-R DASA-IPC 2022 067 (EUCT 2023-505846-24-00), currently enrolling VEN-R patients.British journal of haematologyhttps://www.ebi.ac.uk/biostudies/studies/S-EPMC12378904biostudies-literatureDasatinib overcomes AML cells resistant to BCL2 inhibition by degrading MCL1.PMC12378904AMX-21-PEP-018Adelaide JJacquel AHospital MABertucci FMontersino CAuberger PGarciaz SCollette YChaffanet MVey NGuille ACastellano RBourgoin MfalseDasatinib overcomes AML cells resistant to BCL2 inhibition by degrading MCL1.Acute myeloid leukaemia (AML) is a severe disease occurring mainly in the elderly population. Venetoclax (VEN) combined with azacitidine has changed the paradigm of treatment of AML. Nevertheless, approximately 30% of patients are primary refractory to VEN (VEN-R), with no current therapeutic option. To target VEN-R AML, we collected primary blasts at AML diagnosis in a prospective biobanking trial (NCT02320656). We performed targeted Next Generation Sequencing and ex vivo drug testing in 108 AML samples. We noticed that 17 (15.7%) were navitoclax-resistant (NAV-R). We observed a strong anticorrelation between NAV and Dasatinib (DASA) ex vivo sensitivity, also found in the BEAT-AML cohort. As NAV and ABT797 are both BCL2/BCLxL inhibitors, we hypothesized that blasts sensitive to DASA (DASA-S) were dependent on MCL1. We performed BH3 profiling in 25 samples confirming MCL1 dependency. Immunoblots showed a higher MCL1 and BIM protein expression. We found a dose-dependent decrease in MCL1 protein expression associated with caspase 3 activation upon DASA in a primary AML sample. Collectively, these results suggest that DASA degrades MCL1 and effectively kills AML cells. To prove this hypothesis, we designed a phase II clinical trial named VEN-R DASA-IPC 2022 067 (EUCT 2023-505846-24-00), currently enrolling VEN-R patients.2025-01-01T00:00:00Z2025 Jun2026-05-09T17:56:43.981Z2026-04-08T01:07:14.544ZS-EPMC123789044047479710.1111/bjh.20195