RAS activation induces synthetic lethality of MEK inhibition with mitochondrial oxidative metabolism in acute myeloid leukemia
Justine Decroocq, Rudy Birsen, Camille Montersino, Prasad Chaskar, Jordi Mano, Laury Poulain, Chloé Friedrich, Anne‐Sophie Alary, Hélène Guermouche, Ambrine Sahal, Guillemette Fouquet, Mathilde Gotanègre, Federico Simonetta, Sarah Mouche, Pierre Gestraud, Auriane Lescure, Elaine Del Nery, Claudie Bosc, Adrien Grenier, Fetta Mazed, Johanna Mondésir, Nicolas Chapuis, Liza Ho, Aïcha Boughalem, Marc Lelorc’h, Camille Gobeaux, Michaëla Fontenay, Christian Récher, Norbert Vey, Arnaud Guillé, Daniel Birnbaum, Olivier Hermine, Isabelle Radford‐Weiss, Petros Tsantoulis, Yves Collette, Rémy Castellano, Jean‐Emmanuel Sarry, Éric Pasmant, Didier Bouscary, Olivier Kosmider, Jérôme Tamburini
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.