# Novel pro-survival mechanisms of PIM2 in multiple myeloma

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $552,872

## Abstract

Multiple myeloma (MM) comprises 20% of all hematologic malignancies, second only to non-Hodgkin’s
lymphoma, with 34,470 new cases and 12,640 deaths expected in 2022. Despite new therapeutics, MM remains
incurable for almost all patients. The primary cause of treatment failure is upregulation of pro-survival
mechanisms and progressively greater therapy resistance - thus defining these pro-survival responses will
identify key therapeutic targets. The PIM family of serine/threonine kinases (PIM1, PIM2 and PIM3) have been
shown to be oncogenic and overexpressed in a wide range of solid and hematological malignancies, with the
highest level of PIM2 overexpression seen with MM disease progression. PIM kinases are constitutively active,
and because the mRNA and protein have short half-lives their biological activity is dictated by regulation of their
expression. Importantly, it is currently assumed that biological effects of PIM kinases are entirely due to their
kinase activity. Bringing this assumption into question, we recently reported that the first-in-class PIM2-selective
non-ATP-competitive inhibitor JP11646 (JP) caused significantly greater suppression of MM proliferation and
viability compared to ATP-competitive PIM kinase inhibitors that equivalently inhibited PIM2 kinase activity. We
found that JP’s increased efficacy was not due to superior inhibition of kinase activity, but rather to an unexpected
downregulation of PIM2 gene and protein expression that did not occur with the ATP-competitive PIM2 kinase
inhibitors. These observations led to our central hypothesis that PIM2 has critical but previously unrecognized
kinase-independent (Ki) pro-survival function in MM – including maintaining high constitutive expression of the
PIM2 gene. Preliminary studies have found that kinase-dead PIM2 mutants retain significant pro-survival activity.
Mechanistically, we found that PIM2 stably interacts with the oncogene cMYC in MM cells and increases cMYC
binding to several gene promoters - including PIM2 itself. Moreover, a cMYC inhibitor downregulated PIM2
expression, suggesting a novel auto-regulatory loop where PIM2 stabilizes cMYC binding and trans-activation
of the PIM2 promoter – JP, but not ATP-competitive PIM kinase inhibitors, disrupts this loop. Additionally, we
found that SLC25A11 and UCP2 – two genes coding mitochondrial metabolite transporters – are regulated by
PIM2-cMYC axis in MM. Consistent with this, JP treatment or PIM2 knockdown selectively disrupted oxidative
mitochondrial respiration, which we show is dependent on fatty acid oxidation (FAO). We propose to test a novel
model of SLC25A11 and UCP2 overexpression reprogramming MM metabolism to favor FAO and promoting
MM survival. Since JP has similar effects in acute myeloid leukemia and in solid tumors, PIM2 Ki function in MM
may also occur to other cMYC-driven cancers. As such, inhibition of PIM2 Ki function may be a broadly applicable
approach to target oncogenic cMYC activity. The Spec...

## Key facts

- **NIH application ID:** 10823298
- **Project number:** 5R01CA272852-02
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** KELVIN P. LEE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $552,872
- **Award type:** 5
- **Project period:** 2023-04-15 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823298

## Citation

> US National Institutes of Health, RePORTER application 10823298, Novel pro-survival mechanisms of PIM2 in multiple myeloma (5R01CA272852-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10823298. Licensed CC0.

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