Mirk kinase inhibition blocks the in vivo growth of pancreatic cancer cells

Abstract

The Mirk/dyrk1B gene is upregulated and sometimes amplified in pancreatic ductal carcinomas. In poor microenvironmental conditions Mirk mediates cell survival by maintaining cancer cells in a largely quiescent, noncycling state and by decreasing toxic ROS levels through maintaining expression of a series of antioxidant genes. Premature entry into cycle, increased ROS levels, DNA damage, and apoptosis follow Mirk kinase depletion or inhibition. Mirk kinase inhibitor EHT5372 treated Panc1 spheroids lost quiescence markers coincident with an increase in cyclin A showing entry into cycle, and exhibited DNA damage, apoptosis and smaller size. EHT5372 treatment in vivo led to an increased fraction of Ki67 positive, cycling cells in Panc1 xenografts whose size was reduced. Pdx-1-cre LSL/KrasG12D/Ink4a/Arf null B6 mice always develop pancreatic cancer, allowing only 30% survival by 8 weeks, while each of the Mirk kinase inhibitor treated mice survived 8 weeks. Mirk inhibition led to a roughly four-fold increase in tumor αSMA-positive fibroblasts and large stromal collagen-rich infiltrates in the pancreas that can restrain tumor growth. The mTOR inhibitor RAD001 alone, or together with EHT5372, reduced pancreatic cancer size 30-fold, while the drug combination reduced the number of microscopic tumor foci 2-fold compared to RAD001 alone.

DYRK1B as therapeutic target in Hedgehog/GLI-dependent cancer cells with Smoothened inhibitor resistance

“…Using SMO-inhibitor resistant pancreatic cancer cells we also confirm a previous report showing that DYRK1B targeting in pancreatic cancer cells has pronounced therapeutic efficacy in vitro and in vivo , though the molecular mechanisms including the link to HH/GLI signaling remained unidentified in this study [ 56 ]. In the present study we show that interfering with DYRK1B dramatically impairs SMO-independent GLI1 expression in RAS mutant pancreatic cancer cells and phenocopies the anti-tumorigenic effect of GLI1 targeting [ 16 ].…”

Targeting DYRK1B suppresses the proliferation and migration of liposarcoma cells

“…Kaplan-Meier survival curve analysis showed that well-differentiated liposarcoma patients have a better prognosis than other pathology subtypes [ 35 ]. These findings validate previous reports that amplified expression of DYRK1B is involved in the progression of certain cancers and associated with poor prognosis [ 36 – 40 ]. We then investigated the function roles of DYRK1B in liposarcoma cells.…”

“…DYRK1B facilitates skeletal myoblast differentiation and survival by mediating cell cycle arrested in G 0 phase and exerting anti-apoptotic effect [ 21 , 22 ]. More importantly, DYRK1B is overexpressed and highly activated in many types of solid tumors, including pancreatic, lung, ovarian, colon cancer, rhabdomyosarcoma and osteosarcoma [ 23 – 28 ]. On the other hand, emerging insights into DYRK1B promotion adipogenesis and involvement in metabolic syndrome suggest that DYRK1B may potentially relevant to fat cell malignancy [ 29 ].…”

Non-Genomic Androgen Action Regulates Proliferative/Migratory Signaling in Stromal Cells

“…Hence, the arguments put forward here raise the possibility that androgens elicit anti-proliferative signals in human cancers bearing oncogenic Ras mutations through activation of DYRK 1B. Noteworthy, DYRK 1B is an active kinase in various human cancers and regulates Ras-driven transformation and tumor progression ( 38 – 40 ). Thus, by activating DYRK 1B kinase, androgen/AR axis might restrain Ras-driven transformation.…”