Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• Constitutive Janus kinase 2 (JAK2) signaling drives myeloproliferative neoplasms (MPNs).
• Current JAK2 inhibitors show limited therapeutic efficacy due to compensatory signaling pathways.
• MEK/ERK signaling is implicated in MPN cell survival and resistance to JAK inhibition.

Purpose of the Study:

• To investigate the role of MEK/ERK signaling in MPN cell survival during JAK inhibition.
• To identify mechanisms maintaining ERK activation in vivo despite JAK2 inhibition.
• To evaluate the therapeutic potential of combined JAK/MEK inhibition in MPNs.

Main Methods:

• In vitro and in vivo studies using MPN cell lines and mouse models (Jak2V617F, MPLW515L).
• Assessment of JAK2, MEK, and ERK signaling pathways following JAK inhibition.
• Identification of key kinases and ligands involved in compensatory signaling.
• Evaluation of combined JAK/MEK inhibition efficacy and impact on MPN reversal.

Main Results:

• JAK2 inhibition suppressed MEK/ERK activation in vitro but not in vivo, indicating cell-extrinsic factors maintain ERK activation.
• Platelet-derived growth factor receptor alpha (PDGFRα) and its ligands (PDGF-AA/BB) were identified as key mediators of persistent ERK activation.
• PDGF-BB acted as a bypass mechanism for ERK activation in the presence of ruxolitinib.
• Combined JAK/MEK inhibition effectively suppressed MEK/ERK signaling in vivo, leading to increased efficacy and fibrosis reversal.

Conclusions:

• Compensatory ERK activation via PDGFRα signaling limits the efficacy of JAK2 inhibitors in MPNs.
• Dual JAK/MEK inhibition represents a promising therapeutic strategy for MPNs.
• This approach may also benefit other malignancies driven by aberrant JAK-STAT signaling.