Abstract
Although conventional therapies for acute myeloid leukemia (AML) and diffuse large B-cell lymphoma (DLBCL) are effective in inducing remission, many patients relapse upon treatment. Hence, there is an urgent need for novel therapies. 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, we performed an shRNA-based genetic screen to identify kinases whose suppression is synergistic with PIM inhibition. Here, we report that suppression of p38α (MAPK14) is synthetic lethal with the PIM kinase inhibitor AZD1208. PIM inhibition elevates reactive oxygen species (ROS) levels, which subsequently activates p38α and downstream AKT/mTOR signaling. We found that p38α inhibitors sensitize hematological tumor cell lines to AZD1208 treatment in vitro and in vivo. These results were validated in ex vivo patient-derived AML cells. Our 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.
Highlights
Cancer cells are highly dependent on oncogenic signaling, making targeted agents that inhibit these pathways an attractive treatment option
PIM kinases (PIM1, -2, and -3) are a family of short-lived, constitutively active serine/threonine kinases which are often overexpressed in hematological tumors, including acute myeloid leukemia (AML), chronic myeloid leukemia (CML), the activated B-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), and multiple myeloma (MM) [2,3,4,5,6]
Only the sensitive cell lines demonstrated reduced phosphorylation of PRAS40, S6, and 4EBP1. Since these targets are regulated by mTOR, resistance might occur through sustained mTOR signaling upon PIM inhibition
Summary
Cancer cells are highly dependent on oncogenic signaling, making targeted agents that inhibit these pathways an attractive treatment option. Many potentially useful agents will not make it through early phase clinical trials It is essential, even before the start of clinical studies, to identify powerful drug combinations that prevent therapy resistance. Even before the start of clinical studies, to identify powerful drug combinations that prevent therapy resistance One such promising class of drugs currently being evaluated in phase I clinical trials are the PIM kinase inhibitors (NCT01588548, NCT01489722, NCT02078609, and NCT02160951). 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 [7,8,9]. 30 percent of AML www.impactjournals.com/oncotarget patients harbor the FLT3 internal tandem duplication (FLT-ITD), which results in high JAK/STAT signaling and PIM overexpression [10,11,12]. The transcription factors NF-κB and HOXA9 can regulate PIM expression and are often highly active in AML [1315]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
