Hypoxia-Inducible PIM Kinase Expression Promotes Resistance to Antiangiogenic Agents

Abstract

Purpose: Patients develop resistance to anti-angiogenic drugs, secondary to changes in the tumor microenvironment, including hypoxia. PIM kinases are pro-survival kinases and their expression increases in hypoxia. The goal of this study was to determine whether targeting hypoxia-induced PIM kinase expression is effective in combination with VEGF-targeting agents. The rationale for this therapeutic approach is based on the fact that anti-angiogenic drugs can make tumors hypoxic, and thus more sensitive to PIM inhibitors. Experimental Design: Xenograft and orthotopic models of prostate and colon cancer were used to assess the effect of PIM activation on the efficacy of VEGF-targeting agents. Immunohistochemistry and in vivo imaging were used to analyze angiogenesis, apoptosis, proliferation, and metastasis. Biochemical studies were performed to characterize the novel signaling pathway linking PIM and HIF-1. Results: PIM was upregulated following treatment with anti-VEGF therapies, and PIM1 overexpression reduced the ability of these drugs to disrupt vasculature and block tumor growth. PIM inhibitors reduced HIF-1 activity, opposing the shift to a pro-angiogenic gene signature associated with hypoxia. Combined inhibition of PIM and VEGF produced a synergistic anti­tumor response characterized by decreased proliferation, reduced tumor vasculature, and decreased metastasis. Conclusions: This study describes PIM kinase expression as a novel mechanism of resistance to anti-angiogenic agents. Our data provide justification for combining PIM and VEGF inhibitors to treat solid tumors. The unique ability of PIM inhibitors to concomitantly target HIF-1 and selectively kill hypoxic tumor cells addresses two major components of tumor progression and therapeutic resistance.

PIM protein kinases regulate the level of the long noncoding RNA H19 to control stem cell gene transcription and modulate tumor growth

“…The promoter region of H19 contains transcription factor binding sites for HIF1 (Wu et al , 2017), androgen receptor (AR; putative), E2F1 (Berteaux et al , 2005), and OCT‐4/SOX2 (Zimmerman et al , 2013). In hypoxia, PIM kinases are elevated and increase HIF1 activity (Casillas et al , 2018), thus having the potential to activate H19 transcription. H19 levels have been shown to be hormonally regulated and are inhibited by dihydrotestosterone in androgen‐responsive cells (Berteaux et al , 2004), thus pointing to an inverse relation between AR and H19.…”

Hypoxia-Induced PIM Kinase and Laminin-Activated Integrin α6 Mediate Resistance to PI3K Inhibitors in Bone-Metastatic CRPC

“…Hypoxia is known to promote drug resistance through pleotropic mechanisms. Our group recently described the importance of hypoxia-inducible PIM kinase signaling for prostate cancer cell survival in hypoxia via induction of Nrf2 [26,48]. Because PIM levels are significantly upregulated in hypoxia, we examined PIM1 expression in subcutaneous and bone-resident PC3 and LuCaP tumor sections to determine whether PIM1 is also preferentially activated in the bone TME.…”

Identification of PIM1 substrates reveals a role for NDRG1 in prostate cancer cellular migration and invasion

“…PIM1 is constitutively active and does not depend upon post-translational modifications for activation 3,4 . As such, PIM1 is regulated primarily by transcription, including induction by cytokines through the JAK/STAT pathway 5 and by hypoxia 6 . PIM1 protein levels are also regulated translationally via its 5' UTR 7 and by the microRNA miR-33a 8 .…”