Autophagy contributes to resistance to ruxolitinib in myeloproliferative neoplasms
Protein Phosphatase 2A,
The Janus kinase 2 (JAK2)-driven myeloproliferative neoplasms (MPNs) are chronic malignancies associated with high-risk complications and limited responses to JAK inhibitors such as ruxolitinib. A better understanding of cellular changes induced by ruxolitinib is required to develop new combinatory therapies to improve treatment efficacy. Here, we demonstrate that PP2A-dependent autophagy mediated by JAK2 activity inhibition contributes to resistance to ruxolitinib. Indeed, inhibition of autophagy or PP2A activity, in vitro, along with ruxolitinib treatment increases ruxolitinib efficacy. Moreover, using in vivo the autophagy inhibitor Lys05, together with ruxolitinib, improved leukemia burden reduction and significantly prolonged the mice’s overall survival compared with ruxolitinib alone. Altogether, our data support that targeting autophagy or its identified regulator PP2A could enhance sensitivity to ruxolitinib of JAK2V617F MPN cells and improve MPN patient care. Clinical trials combining ruxolitinib with an autophagy inhibitor are planned.
This work opens up several perspectives.
Our data indicate that inhibiting autophagy in MPN JAK2V617F patients may selectively target malignant hematopoietic cells. It is an important point that need to be further confirmed since it is why ruxolitinib has important toxic side effects, as well as a limited efficacy, because it inhibits both wild type and mutated JAK.
Another possibility to reduce side effects, is the identification of which specific subsets of PP2A are responsible for ruxolitinib-induced autophagy in order to target specifically the correct PP2A complex rather than all PP2A complexes.
Discover the published article
Blood Cancer J. 2023 Jul 10;13(1):106.doi: 10.1038/s41408-023-00875-x.
Targeting PP2A-dependent autophagy enhances sensitivity to ruxolitinib in JAK2V617F myeloproliferative neoplasms
Charly Courdy, Loïc Platteeuw, Charlotte Ducau, Isabelle De Araujo, Emeline Boet, Ambrine Sahal, Estelle Saland, Valérie Edmond, Suzanne Tavitian, Sarah Bertoli, Pierre Cougoul, Fanny Granat, Laura Poillet, Caroline Marty, Isabelle Plo, Jean-Emmanuel Sarry, Stéphane Manenti, Véronique Mansat-De Mas, Carine Joffre
Toulouse Cancer Research Center (Oncopole)
Toulouse - FR
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