PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Luszczak, Sabina; Kumar, Christopher; Sathyadevan, Vignesh Krishna; Simpson, Benjamin S.; Gately, Kathy; Whitaker, Hayley C.; Heavey, Susan

doi:10.1038/s41392-020-0109-y

Cited by 61 publications

(54 citation statements)

References 139 publications

(212 reference statements)

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“…Inducing Pim1 with DOX in this tumor cell line caused an increase in EDC3 phosphorylation (Fig 3C). This increase was similar to that of the ribosomal protein S6, which is a downstream target of Pim regulation of mTORC1 (Zhang et al , 2009; Padi et al , 2019; Luszczak et al , 2020). The addition of Pim447 to these cells reversed the effect of Pim1 overexpression, eliminating phosphorylation.…”

Section: Resultssupporting

confidence: 53%

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

et al. 2021

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Regulation of mRNA stability and translation plays a critical role in determining protein abundance within cells. Processing bodies (P‐bodies) are critical regulators of these processes. Here, we report that the Pim1 and 3 protein kinases bind to the P‐body protein enhancer of mRNA decapping 3 (EDC3) and phosphorylate EDC3 on serine (S)161, thereby modifying P‐body assembly. EDC3 phosphorylation is highly elevated in many tumor types, is reduced upon treatment of cells with kinase inhibitors, and blocks the localization of EDC3 to P‐bodies. Prostate cancer cells harboring an EDC3 S161A mutation show markedly decreased growth, migration, and invasion in tissue culture and in xenograft models. Consistent with these phenotypic changes, the expression of integrin β1 and α6 mRNA and protein is reduced in these mutated cells. These results demonstrate that EDC3 phosphorylation regulates multiple cancer‐relevant functions and suggest that modulation of P‐body activity may represent a new paradigm for cancer treatment.

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Section: Resultssupporting

confidence: 53%

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

et al. 2021

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“…The PIM and PI3K/mTOR pathways are interconnected, with each pathway influencing the signalling and activity of the other 12 . There is a significant overlap of cellular functions of PIM and AKT 6 .…”

Section: Introductionmentioning

confidence: 99%

“…c-MYC is also upregulated by both PIM and mTOR 6 . This relationship gives rise to the development of resistance to treatment, as the pathways can bypass the inhibition by compensating for loss of signalling of either one 12 , 15 , 16 .…”

Section: Introductionmentioning

confidence: 99%

“…AUM302, a novel triple PIM/PI3K/mTOR inhibitor, has recently been shown to increase cell differentiation, downregulate n-MYC, induce apoptosis and decrease cell viability in neuroblastoma 20 . Co-targeting of PIM and PI3K has been attempted in prostate cancer using different combinations of drugs 12 , 19 ; these studies suggest that co-targeting PIM and PI3K could offer superior clinical outcomes to targeting either alone.…”

Section: Introductionmentioning

confidence: 99%

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Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

Luszczak

Simpson

Stopka‐Farooqui

et al. 2020

Sci Rep

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PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common effectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efficacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥ Gleason 8). A co-targeted inhibition approach offered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 + BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies. Prostate cancer remains as the leading cause of cancer-related death for men 1. Most current therapies exhibit issues with significant side effects, therefore it is crucial to develop lower toxicity therapeutics which would reduce the impact of treatment on patients' lives. Overexpression of the PIM family in prostate cancer has been found to lead to increased tumorigenicity and faster progression of the disease due to its impact on metastasis formation, invasion and migration 2-4. Clinically, PIM can lead to decreased overall survival, insensitivity to cancer treatment and increased proliferation 5. Its effect is mainly mediated by interactions with other pathways including PI3K/mTOR (Phosphoinositide 3-kinase; mammalian target of rapamycin), and various downstream effectors 2,6,7. The PI3K/mTOR pathway deregulation in cancer correlates with disease progression 8 and impacts on apoptosis, survival and cell growth 6. The PI3K pathway also regulates multiple oncogenes and tumour suppressor genes 8. Despite being an attractive pathway for anti-cancer drug targeting, results from monotherapeutic PI3K inhibition strategies have been disappointing, with the growing consensus being that improved co-targeting strategies are warranted 9-11 .

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“… 5 Preclinical studies revealed biological pathways implicated in tumorigenesis and therapy resistance, such as NF-kB, PI3K/mTOR, and WNT/β-catenin. 6 – 9 However, in preclinical studies, cell culture of primary osteosarcoma cells or cell lines undergo extensive genetic changes and lose their phenotypic heterogeneity; thus, the conclusions from studies made with these cells are different from those of the primary tumors. Single-cell transcriptomics technologies can reveal cellular heterogeneity within a cell population.…”

Section: Introductionmentioning

confidence: 99%

Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma

Wang

Huang

You

et al. 2020

Sig Transduct Target Ther

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The adaptation of osteosarcoma cells to therapeutic pressure impedes the efficacy of chemotherapy for osteosarcoma. However, the characteristics and cellular organization of therapy-resistant cells in osteosarcoma tumors remain elusive. Here, we utilized single-cell transcriptomics to systematically map the cell-type-specific gene expression in a chemotherapy-resistant osteosarcoma tumor. Our data demonstrated the VEGFR2-JMJD3-abundant subsets as quiescent stem-like cells, thereby establishing the hierarchy of therapy-resistant actively cycling progenitor pools (JMJD3-abundant) in osteosarcoma. VEGFR2 inhibitor and JMJD3 inhibitor synergistically impeded osteosarcoma cell propagation and tumor growth. Although osteosarcoma cells are predisposed to apoptosis induced by the synergistic therapy through activation of the CHOP pro-apoptotic factor via the endoplasmic reticulum (ER) stress, the stem-like/progenitor cells exhibit an adaptive response, leading to their survival. Reduction in cellular glutathione levels in stem-like/progenitor cells caused by the treatment with a glutathione synthesis inhibitor increases ER stress-induced apoptosis. Importantly, the marked therapeutic improvement of synergistic therapy against stem-like/progenitor cells was achieved by using glutathione-scavenging nanoparticles, which can load and release the drug pair effectively. Overall, our study provides a framework for understanding glutathione signaling as one of the therapeutic vulnerabilities of stem-like/progenitor cells. Broadly, these findings revealed a promising arsenal by encapsulating glutathione-scavenging nanoparticles with co-targeting VEGFR2 and JMJD3 to eradicate chemotherapy-resistant osteosarcoma.

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PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

Cited by 61 publications

References 139 publications

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

EDC3 phosphorylation regulates growth and invasion through controlling P‐body formation and dynamics

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

Nanoparticle enhanced combination therapy for stem-like progenitors defined by single-cell transcriptomics in chemotherapy-resistant osteosarcoma

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