PIM1 kinase inhibition as a targeted therapy against triple-negative breast tumors with elevated MYC expression

Abstract

Triple-negative breast cancer (TNBC), which lacks the expression of the estrogen, progesterone, and HER2 receptors, represents the breast cancer subtype with the poorest outcome1. No targeted therapy is available against this subtype due to lack of validated molecular targets. We previously reported that MYC signaling is disproportionally elevated in triple-negative (TN) tumors compared to receptor-positive (RP) tumors2. MYC is an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes3. Direct inhibition of oncogenic MYC transcriptional activity has remained challenging4,5. The present study conducted an shRNA screen against all kinases to uncover novel MYC-dependent synthetic lethal combinations, and identified PIM1, a non-essential kinase. Here we demonstrate that PIM1 expression was elevated in TN tumors and was associated with poor prognosis in patients with hormone and HER2 receptor-negative tumors. Small molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic breast cancer models by inhibiting oncogenic transcriptional activity of MYC while simultaneously restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that exhibit elevated MYC expression.

PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer

“…We found that PIM1 knockdown upregulated CDKN1B/ p27, suggesting a mechanism by which PIM1 promotes cell cycle progression in TNBC. Our findings concord with the findings from Horiuchi et al 43 (personal communication) and indeed, others have shown that PIM1 downregulates p27 at transcriptional and post-transcriptional levels 37 in other contexts. We show for the first time that PIM1 knockdown decreased the expression of PTPN11 and EPHA2, genes of significant relevance in breast cancer 15,16 : PTPN11, encodes phosphatase SHP2, involved in breast cancer progression and maintainance of tumor-initiating cells 15 .…”

“…PIM1 knockdown downregulated transcription of a subset of MYC-target genes including MCL1 through mechanisms such as phosphorylation of Histone-H3 at Ser10 and phosphorylation of c-MYC at Ser62, known to be required for c-MYC-driven transcriptional activation and oncogenic transformation 10,30 . Altogether, our data support PIM1 as a potential target in basal-like TNBCs, including the MYC-driven group, and are supported by the independent study by Horiuchi et al 43 (personal communication), which demonstrates that c-MYC overexpression generates PIM1 essentiality in mammary epithelial cells and further proposes that PIM1 function is needed to support c-MYC-dependent malignancy in TNBC cells 43 .…”

“…Herein we show that MCL1 expression is increased upon exogenous expression of Myc in TNBC, and that PIM1 regulates c-MYC transcriptional activity specifically, including MCL1 expression levels. PIM1 was shown to phosphorylate the BCL2-partner BAD in leukemia 11 and kidney COS-7 cells 25 and this is now been demonstrated in TNBC by Horiuchi et al 43 . Herein, we specifically elucidated a role of PIM1 in raising the TNBC cell's threshold for mitochondrial-mediated apoptosis, and that this can be mediated by BCL2-family members, providing insight to the mechanisms by which PIM1 might overcome oncogene-induced and chemotherapy-induced apoptosis.…”

PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

“…Moreover, PIM2 overexpression in mice could promote breast cancer tumorigenesis (Jimenez‐Garcia et al ., ). But the mechanisms of PIM2 by which regulates breast cancer cell proliferation are still unclear, Our data showed that PIM2 was crucial in the regulation of TTP‐reduced proliferation and migration in breast cancer cells, consistent with previous studies (Horiuchi et al ., ).…”

Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer

“…phosphorylating the inhibitory site Ser83 on ASK1 (25), and PIM1 has been correlated with tumor aggressiveness and poor survival in TNBC (62). Combining NOS inhibition therapy with docetaxel may prevent activation of PIM1, resulting in a decrease of pASK1 Ser83 levels and an increase in pASK1 Thr845 levels, which result in activation of effector proteins JNK and cleaved caspases 3 and 9 (Fig.…”