Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer

Malone, Tom; Schäfer, Lea; Simon, Nathalie; Heavey, Susan; Cuffe, Sinéad; Finn, Stephen; Moore, Gillian; Gately, Kathy

doi:10.1016/j.pharmthera.2019.107454

Cited by 26 publications

(30 citation statements)

References 172 publications

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“…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%

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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Section: Introductionmentioning

confidence: 99%

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

Self Cite

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“…Our results prove that PIM-1 may function as an oncogene in CC, and PIM-1 may exert its carcinogenic effects through activating the EGFR signaling via increasing the proliferation and decreasing the apoptosis of CC cells. The PIM kinases were first reported as most significantly up-regulated genes during the process of embryonic development 9,15 ; however, in recent years, PIMs were also found to be over-expressed in several cancers. The role of PIM-1 as an oncogene has been investigated in different studies.…”

Section: Discussionmentioning

confidence: 99%

“…The PIM kinase family is comprised of three proteins, including PIM-1, PIM -2, and PIM-3. 9 It has been reported that different transcription factors can recruit PIM-1 to the…”

Section: Introductionmentioning

confidence: 99%

PIM-1 may function as an oncogene in cervical cancer via activating the EGFR signaling

Yang

Dong

et al. 2020

Int J Biol Markers

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Background: This work was designed to explore the roles of PIM-1 in the development of cervical cancer. Methods: There were 90 paired cervical tumor samples and the non-tumor adjacent tissue. The levels of PIM-1 in different samples were examined using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) methods. The potential diagnostic value of PIM-1 was analyzed by the receiver operating characteristic (ROC) curve; furthermore, the expression of EGFR in tumor samples was detected, and Pearson’s correlation analysis was performed to analyze the relationship between the expression of PIM-1 and EGFR. Finally, cervical cancer cell line Hela cells were cultured and treated by PIM-1 siRNA, and MTT assay and Pi/Annexin V assay were performed to explore the effects of PIM-1 siRNA on the growth and apoptosis ability of the Hela cells. Results: PIM-1 was significantly up-regulated in cervical cancer tissue compared to adjacent tissue, and the expression of PIM-1 in patients with cervical cancer is positively associated with the size and metastasis of the tumor. ROC analysis showed PIM-1 is a sensitive biomarker for the diagnosis of cervical cancer. Furthermore, EGFR was over-expressed in cervical cancer tumor tissues, and the levels of PIM-1 and EGFR in cervical cancer tissue were positively correlated. Finally, PIM-1 siRNA dramatically inhibited the viability and promoted the apoptosis of the Hela cells. Conclusion: Our findings prove that PIM-1 may function as an oncogene in cervical cancer and can regulate the EGFR signaling in cervical cancer.

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“…The Proviral integration site for Moloney murine leukemia virus (PIM) kinases are a family of serine-threonine kinases that are known to promote tumorigenesis by impacting cell cycle progression, survival, and proliferation (Malone et al, 2020; Nawijn et al, 2011). Pim1 expression is elevated in ~50% of human prostate cancer specimens, particularly in high Gleason grade and aggressive metastatic prostate cancer cases, highlighting its ability to enhance tumorigenesis (Chen et al, 2005; Dhanasekaran et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors

Casillas

Chauhan

Toth

et al. 2021

Preprint

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SummaryAngiogenesis is essential for sustained growth of solid tumors. Hypoxia-inducible factor 1 (HIF-1) is a master regulator of angiogenesis and constitutive activation of HIF-1 is frequently observed in human cancers. Thus, understanding mechanisms governing the activation of HIF-1 is critical for successful therapeutic targeting of tumor angiogenesis. Herein, we establish a new regulatory mechanism responsible for the constitutive activation of HIF-1α in cancer, irrespective of oxygen tension. PIM1 kinase directly phosphorylates HIF-1α at threonine 455, a previously uncharacterized site within its oxygen-dependent degradation domain. This phosphorylation event disrupts the ability of prolyl hydroxylases (PHDs) to bind and hydroxylate HIF-1α, interrupting its canonical degradation pathway and promoting constitutive transcription of HIF-1 target genes. Overexpression of PIM1 is sufficient to stabilize HIF-1α in normoxia and stimulate angiogenesis in a HIF-1-dependent manner in vivo. CRISPR mutants of HIF-1α (Thr455D) showed increased tumor growth, proliferation and angiogenesis. Moreover, T455D xenograft tumors were refractory to the anti-angiogenic and cytotoxic effects of PIM inhibitors. These data identify a new signaling axis responsible for hypoxia-independent activation of HIF-1 and expand our understanding of the tumorigenic role of PIM1 in solid tumors.

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Current perspectives on targeting PIM kinases to overcome mechanisms of drug resistance and immune evasion in cancer

Cited by 26 publications

References 172 publications

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

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

PIM-1 may function as an oncogene in cervical cancer via activating the EGFR signaling

Direct phosphorylation and stabilization of HIF-1α by PIM1 kinase drives angiogenesis in solid tumors

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