학술논문
RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia
Document Type
Original Paper
Author
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
Source
Leukemia. 36(5):1237-1252
Subject
Language
English
ISSN
0887-6924
1476-5551
1476-5551
Abstract
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.