ASH 2024 | Targetting aberrant DUSP6-RSK1 signaling in MPNs to avoid treatment resistance & disease progression

So this afternoon at the scientific workshop, I will be speaking about our work related to a signaling axis driven by DUSP6 and RSK1, which we have found to be important in driving myeloproliferative disease development and progression to secondary acute myeloid leukemia. 

This work was really focused on trying to understand what drives disease progression in myeloproliferative neoplasms, and we initially found that this phosphatase DUSP6 was specifically upregulated in its expression in patients who had progressed to secondary AML. We then went on to demonstrate that this phosphatase DUSP6 is really a critical driver such that if you target it genetically or pharmacologically, it seems to reduce the disease features in our animal models. Subsequently, we looked downstream at this kinase RSK1, which is regulated in part by DUSP6. And we found that this was also a targetable dependency in these diseases. And in particular, utilizing a compound called PMD-026, which is an orally available pan-RSK inhibitor, we found that targeting RSK kinases with this compound resulted in potent efficacy in our animal models, not just in MPNs, but across myeloid malignancies, including acute myeloid leukemia. 

So we’re really excited about the potential translational implications of this work. This compound, PMD-026, is currently in Phase II clinical trials in breast cancer and we’re working closely with the company Phoenix Molecular Designs to move forward with studies in hematological malignancies including MPNs and AML.

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