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Article Dans Une Revue Leukemia Année : 2022

RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia

Rudy Birsen
  • Fonction : Auteur
Prasad Chaskar
  • Fonction : Auteur
Jordi Mano
  • Fonction : Auteur
Laury Poulain
  • Fonction : Auteur
Chloé Friedrich
  • Fonction : Auteur
Sarah Mouche
  • Fonction : Auteur
Adrien Grenier
  • Fonction : Auteur
Liza Ho
  • Fonction : Auteur
Marc Lelorc'H
  • Fonction : Auteur
Petros Tsantoulis
  • Fonction : Auteur

Résumé

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 PTPN11 genes). 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.

Dates et versions

hal-04085323 , version 1 (28-04-2023)

Identifiants

Citer

Justine Decroocq, Rudy Birsen, Camille Montersino, Prasad Chaskar, Jordi Mano, et al.. RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia. Leukemia, 2022, 36 (5), pp.1237-1252. ⟨10.1038/s41375-022-01541-0⟩. ⟨hal-04085323⟩
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