Oncotarget

Interview with Dr. Bernards & Diede Brunen from the Netherlands Cancer Institute

Oncotarget published "Intrinsic resistance to PIM kinase inhibition in AML through p38α-mediated feedback activation of mTOR signaling" which reported that PIM kinases are often overexpressed in AML and DLBCL and are therefore an attractive therapeutic target.

However, in vitro experiments have demonstrated that intrinsic resistance to PIM inhibition is common.

It is therefore likely that only a minority of patients will benefit from single agent PIM inhibitor treatment.

In this study, the authors performed an shRNA-based genetic screen to identify kinases whose suppression is synergistic with PIM inhibition.

Here, they report that suppression of p38α is synthetic lethal with the PIM kinase inhibitor AZD1208. PIM inhibition elevates reactive oxygen species levels, which subsequently activates p38α and downstream AKT/mTOR signaling. They found that p38α inhibitors sensitize hematological tumor cell lines to AZD1208 treatment in vitro and in vivo.

These findings provide mechanistic and translational evidence supporting the rationale to test a combination of p38α and PIM inhibitors in clinical trials for AML and DLBCL.

Dr. René Bernards from The Netherlands Cancer Institute said, "Cancer cells are highly dependent on oncogenic signaling, making targeted agents that specifically inhibit these pathways an attractive treatment option."

"Cancer cells are highly dependent on oncogenic signaling, making targeted agents that specifically inhibit these pathways an attractive treatment option."

One such promising class of drugs currently being evaluated in phase I clinical trials are the PIM kinase inhibitors.

PIM kinases are a family of short-lived, constitutively active serine/threonine kinases which are often overexpressed in hematological tumors, including acute myeloid leukemia, chronic myeloid leukemia, the activated B-like subtype of diffuse large B-cell lymphoma, and multiple myeloma.

The expression of PIM kinases is largely regulated via the JAK/STAT pathway on a transcriptional level, since PIM kinases have a short half-life.

Figure 6: Schematic overview of feedback activation of mTOR signaling upon PIM inhibition.

Figure 6: Schematic overview of feedback activation of mTOR signaling upon PIM inhibition. AZD1208 treatment inhibits PIM activity; thereby elevating ROS levels which subsequently results in resistance through activation of p38, AKT, and mTOR signaling. Combined treatment of AZD1208 with either a p38 inhibitor (SCIO-469) or an AKT inhibitor (MK2206) prevents feedback activation of mTOR and restores PIM inhibitor sensitivity. Single mTOR inhibitor treatment (AZD8055) also prevents cell growth, indicating the dependency of hematopoietic tumor cells to this pathway.

PIM kinases are highly redundant and regulate the activity of substrates involved in translation, survival, cell cycle, and MYC-dependent transcription.

PIM kinases contain a unique ATP-binding pocket, which has resulted in the development of highly selective pan-PIM inhibitors such as AZD1208.

The Bernards Research Team concluded in their Oncotarget Research Output that their results are in concordance with previous findings showing synergy between PIM and PI3K or AKT inhibitors.

However, these studies lacked insights in the mechanism underlying this synergistic interaction.

Even more important, p38 inhibitors - which are in clinical trial for diseases such as rheumatoid arthritis, chronic obstructive pulmonary disease, and multiple myeloma - are likely less toxic than PI3K, AKT, and mTOR inhibitors and could therefore be preferred for combination therapies.

Lower toxicity is particularly important since these targeted agents will likely be used on top of a chemotherapeutic backbone.

To conclude, these findings suggest that AML patients might benefit from combined PIM and p38 inhibitor treatment.

DOI - https://doi.org/10.18632/oncotarget.9822

Full text - https://www.oncotarget.com/article/9822/text/

Correspondence to - René Bernards - r.bernards@nki.nl

Keywords - AML, PIM, AZD1208, p38, resistance

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