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Overcoming Disease Persistence in Myeloproliferative Neoplasms (MPN) through Combinatorial Inhibitor Treatment
Max-Planck Innovation
Small molecule
Oncology
Hit To Lead or Lead Optimization
• In combination with pharmacological JAK inhibition, YBX1 inactivation induces apoptosis in JAK2-dependent mouse and primary human patient cells, causing regression of the malignant clones in vivo, and inducing molecular remission.
• Pharmaceutical targeting of downstream pathways regulated by YBX1 (e.g. MEK-ERK-signaling) in combination with JAK-inhibitors in vivo resulted in eradication of JAK2-mutated clones in > 80 %. Consistent with these findings, direct pharmacologic targeting of YBX1 in combination with JAK-inhibitors abrogated ERK-phosphorylation, reduced proliferative capacity and enhanced induction of apoptosis in murine and human JAK2-mutated cells.
• Thus genetic and pharmacologic targeting of YBX1 or its dependent downstream effectors represents a novel therapeutic strategy to target JAK2-mutated clones and overcome disease persistence in JAK2- mutated cancers such as MPNs.
WO2021214303A1
Splicing factor YBX1 mediates persistence of JAK2-mutated neoplasms, Nature. (2020)
