دورية
RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia
| العنوان: | RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia |
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| المؤلفون: | Decroocq, Justine, Birsen, Rudy, Montersino, Camille, Chaskar, Prasad, Mano, Jordi, Poulain, Laury, Friedrich, Chloe, Alary, Anne-Sophie, Guermouche, Helene, Sahal, Ambrine, Fouquet, Guillemette, Gotanègre, Mathilde, Simonetta, Federico, Mouche, Sarah, Gestraud, Pierre, Lescure, Auriane, Del Nery, Elaine, Bosc, Claudie, Grenier, Adrien, Mazed, Fetta, Mondesir, Johanna, Chapuis, Nicolas, Ho, Liza, Boughalem, Aicha, Lelorc’h, Marc, Gobeaux, Camille, Fontenay, Michaela, Recher, Christian, Vey, Norbert, Guillé, Arnaud, Birnbaum, Daniel, Hermine, Olivier, Radford-Weiss, Isabelle, Tsantoulis, Petros, Collette, Yves, Castellano, Rémy, Sarry, Jean-Emmanuel, Pasmant, Eric, Bouscary, Didier, Kosmider, Olivier, Tamburini, Jerome |
| المصدر: | Leukemia; 20220101, Issue: Preprints p1-16, 16p |
| مستخلص: | Despite recent advances in acute myeloid leukemia (AML) molecular characterization and targeted therapies, a majority of AML cases still lack therapeutically actionable targets. In 127 AML cases with unmet therapeutic needs, as defined by the exclusion of ELN favorable cases and of FLT3-ITD mutations, we identified 51 (40%) cases with alterations in RAS pathway genes (RAS+, mostly NF1, NRAS, KRAS,and PTPN11genes). In 79 homogeneously treated AML patients from this cohort, RAS+ status were associated with higher white blood cell count, higher LDH, and reduced survival. In AML models of oncogenic addiction to RAS-MEK signaling, the MEK inhibitor trametinib demonstrated antileukemic activity in vitro and in vivo. However, the efficacy of trametinib was heterogeneous in ex vivo cultures of primary RAS+ AML patient specimens. From repurposing drug screens in RAS-activated AML cells, we identified pyrvinium pamoate, an anti-helminthic agent efficiently inhibiting the growth of RAS+ primary AML cells ex vivo, preferentially in trametinib-resistant PTPN11- or KRAS-mutated samples. Metabolic and genetic complementarity between trametinib and pyrvinium pamoate translated into anti-AML synergy in vitro. Moreover, this combination inhibited the propagation of RA+ AML cells in vivo in mice, indicating a potential for future clinical development of this strategy in AML. |
| قاعدة البيانات: | Supplemental Index |
| تدمد: | 08876924 14765551 |
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| DOI: | 10.1038/s41375-022-01541-0 |