PIM Kinases Are a Potential Prognostic Biomarker and Therapeutic Target in Neuroblastoma

Brunen, Diede; Vries, Romy C de; Lieftink, Cor; Beijersbergen, Roderick L.; Bernards, René

doi:10.1158/1535-7163.mct-17-0868

Cited by 32 publications

(40 citation statements)

References 33 publications

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“…These findings are consistent with previous reports on PI3K inhibition in neuroblastoma (Chesler et al, 2006;Johnsen et al, 2008;Chanthery et al, 2012;Cage et al, 2015). Similarly, PIM inhibition has previously been suggested as a therapeutic option in MYC/MYCN-associated tumor types (Kirschner et al, 2014;Horiuchi et al, 2016;Brunen et al, 2018). Our results of combined PIM/PI3K inhibition effects in neuroblastoma are in line with findings from other tumor types including breast cancer (Le et al, 2016) and glioblastoma (Iqbal et al, 2016).…”

supporting

confidence: 93%

“…Activation of the PIM kinases is thought to be an important PI3K inhibitor resistance mechanism (Le et al , ). While little is known about the role of PIM kinases in neuroblastoma, a recent report suggested that PIMs might serve as prognostic biomarkers and putative treatment targets in this tumor type (Brunen et al , ).…”

Section: Discussionmentioning

confidence: 99%

“…Values are reported as mean AE SEM. n = 2 replicates for LU-NB-2 and LU-NB-3, n = 3 replicates for SK-N-BE (2) role of PIM kinases in neuroblastoma, a recent report suggested that PIMs might serve as prognostic biomarkers and putative treatment targets in this tumor type (Brunen et al, 2018).…”

mentioning

confidence: 99%

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Anti‐tumor effects of PIM / PI 3K/ mTOR triple kinase inhibitor IBL ‐302 in neuroblastoma

et al. 2019

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The PI 3K pathway is a major driver of cancer progression. However, clinical resistance to PI 3K inhibition is common. IBL ‐302 is a novel highly specific triple PIM , PI 3K, and mTOR inhibitor. Screening IBL ‐302 in over 700 cell lines representing 47 tumor types identified neuroblastoma as a strong candidate for PIM / PI 3K/ mTOR inhibition. IBL ‐302 was more effective than single PI 3K inhibition in vitro, and IBL ‐302 treatment of neuroblastoma patient‐derived xenograft ( PDX ) cells induced apoptosis, differentiated tumor cells, and decreased N‐Myc protein levels. IBL ‐302 further enhanced the effect of the common cytotoxic chemotherapies cisplatin, doxorubicin, and etoposide. Global genome, proteome, and phospho‐proteome analyses identified crucial biological processes, including cell motility and apoptosis, targeted by IBL ‐302 treatment. While IBL ‐302 treatment alone reduced tumor growth in vivo , combination therapy with low‐dose cisplatin inhibited neuroblastoma PDX growth. Complementing conventional chemotherapy treatment with PIM / PI 3K/ mTOR inhibition has the potential to improve clinical outcomes and reduce severe late effects in children with high‐risk neuroblastoma.

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supporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Anti‐tumor effects of PIM / PI 3K/ mTOR triple kinase inhibitor IBL ‐302 in neuroblastoma

et al. 2019

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“…Activation of MET has previously been shown to confer resistance to the ALK inhibitor alectinib in NSCLC 31 , and resistance can be overcome with crizotinib, a potent inhibitor of MET 32 . Given substantial evidence in the literature that PIM1 mediates resistance to standard chemotherapy [33][34][35] as well as molecularly targeted agents 36,37 , that high expression of PIM1 is a poor prognostic indicator in multiple cancers [38][39][40] , and that recently Brunen et al 41 . identified PIM kinases as potential therapeutic targets in NF1 wild-type NB, this gene was explored further.…”

Section: Resultsmentioning

confidence: 99%

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

et al. 2019

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Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.

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“…Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) is a serine/threonine kinase, involved in cell cycle progression, cell growth, cell survival and therapy resistance. PIM-1 is activated in various types of cancer, amongst which prostate [14][15][16] , colorectal [15,[17][18][19] , triple negative breast cancer (TNBC) [20,21] , hematologic malignancies [22][23][24] , neuroblastoma [25] and lung cancer [26] . For this reason, PIM kinases could provide a common target for the treatment of diverse malignancies.…”

Section: Introductionmentioning

confidence: 99%

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

Bracht¹,

Karachaliou²,

Berenguer³

et al. 2019

JCMT

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Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds, which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC. Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses, and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and combined with osimertinib in five EGFR-mutation positive NSCLC cell lines. Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3) as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all NSCLC cell lines investigated. Among the EGFR-mutation positive cell lines examined, the H1975 and PC9 cell lines had the highest PIM1 and STAT3 mRNA expression. The combination decreased the osimertinib-induced STAT3 phosphorylation. Conclusion: This study provides a short review on PIM kinases, and shows our results of combined PIM and EGFR inhibition in EGFR-mutation positive NSCLC cell lines. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance.

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PIM Kinases Are a Potential Prognostic Biomarker and Therapeutic Target in Neuroblastoma

Cited by 32 publications

References 33 publications

Anti‐tumor effects of PIM / PI 3K/ mTOR triple kinase inhibitor IBL ‐302 in neuroblastoma

Anti‐tumor effects of PIM / PI 3K/ mTOR triple kinase inhibitor IBL ‐302 in neuroblastoma

The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation positive non-small cell lung cancer

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