The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care

Paíno, Teresa; García-Gómez, Antonio; González-Méndez, Lorena; San-Segundo, Laura; Hernández-García, Susana; López-Iglesias, Ana-Alicia; Algarín, Esperanza M.; Martín-Sánchez, Montserrat; Corbacho, David; Ortiz‐de‐Solórzano, Carlos; Corchete, Luis A.; Gutiérrez, Norma C.; Maetos, María-Victoria; Garayoa, Mercedes; Ocio, Enrique M.

doi:10.1158/1078-0432.ccr-16-0230

Cited by 50 publications

(61 citation statements)

References 46 publications

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“…PIM2 is highly conserved, with >60% sequence identity to PIM1 and PIM3 (Jinesh et al ., ). PIM2 lacks a regulatory domain and thus is constitutively activated, a trait which is used in the design of tumor drugs (Paino et al ., ). PIM2 plays an important role in multiple types of cancer; it is frequently overexpressed in human cancers and promotes cancer‐cell proliferation and survival (An et al ., ).…”

Section: Introductionmentioning

confidence: 99%

PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

et al. 2018

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Tristetraprolin (TTP) is an AU‐rich element‐binding protein that regulates mRNA stability and plays important roles in cancer. The mechanisms by which TTP is regulated in breast cancer are poorly understood. Using multiple biochemical approaches, we found that proviral insertion in murine lymphomas 2 (PIM2) is a novel binding partner of TTP. Interestingly, PIM2 decreased TTP protein levels independent of its kinase activity. PIM2 instead targeted TTP protein for degradation via the ubiquitin‐proteasome pathway. Furthermore, immunohistochemical staining showed that PIM2 and TTP protein levels were negatively correlated in human breast cancer samples. Indeed, PIM2 overexpression de‐repressed TTP‐mediated inhibition of breast cancer cell proliferation and migration in vitro and promoted breast tumor xenograft growth in vivo. These findings demonstrate an important role for the PIM2‐TTP complex in breast cancer tumorigenesis, suggesting that PIM2 may represent a potential therapeutic target for breast cancer treatment.

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Section: Introductionmentioning

confidence: 99%

PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

et al. 2018

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“…AZD1208 is not in clinical development any more [22] and we plan to extend the current work using the pan-PIM inhibitor LGH447 (PIM447). LGH447 has single agent activity, and blocks resistance pathways when combined with standard of care treatments [22,[36][37][38] . The agent is currently being tested in a phase I/II clinical trial (ClinicalTrials.gov Identifier, NCT01456689) for relapsed/ refractory multiple myeloma, and safety and efficacy results are awaited.…”

Section: Discussionmentioning

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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“…Pre‐clinical studies in CLL (Chen et al , 2009c; Decker et al , ; Cervantes‐Gomez et al , ), other haematological malignancies (Garcia et al , ; Keane et al , ; Brunen et al , ; Nair et al , ; Paino et al , ) and solid tumours (Chen et al , 2009b, ; Foulks et al , ; Braso‐Maristany et al , ; O'Hayer et al , ; Warfel et al , ), suggest that, owing to their important roles in tumour cell biology, the PIM family of kinases may represent targets for novel, single agent or combination therapies. This concept is illustrated by a recent study in which the combination of a PIM and a PI3 kinase inhibitor, NMS‐P645 and GDC‐0941 respectively, had significantly more anti‐proliferative activity than either inhibitor alone against pancreatic cancer cells (Mologni et al , ).…”

Section: Discussionmentioning

confidence: 99%

The dual inhibitor of the phosphoinositol‐3 and PIM kinases, IBL‐202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment

et al. 2018

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Despite significant advances in treatment, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Ibrutinib and idelalisib, which inhibit Bruton Tyrosine kinase (BTK) and phosphoinositol-3 (PI3) kinase-δ respectively, have become important treatment options for the disease and demonstrate the potential of targeting components of the B-cell receptor-signalling pathway. IBL-202 is a dual inhibitor of the PIM and PI3 kinases. Synergy between the pan-PIM inhibitor, pPIMi, and idelalisib against a range of haematological cell lines and primary CLL cells supports the rationale for preclinical studies of IBL-202 in CLL. Importantly, IBL-202, but not idelalisib, was cytotoxic against CLL cells under in vitro conditions that mimic the hypoxic tumour microenvironment. The significant effects of IBL-202 on CD49d and CXCR4 expression and migration, cycle and proliferation of CLL cells suggest the drug may also interfere with the migratory and proliferative capacity of the leukaemic cells. Collectively, these data demonstrate that dual inhibition of the PIM and PI3 kinases by IBL-202 may be an effective strategy for targeting CLL cells, particularly within the environmental niches known to confer drug-resistance.

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The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care

Cited by 50 publications

References 46 publications

PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

PIM2 interacts with tristetraprolin and promotes breast cancer tumorigenesis

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

The dual inhibitor of the phosphoinositol‐3 and PIM kinases, IBL‐202, is effective against chronic lymphocytic leukaemia cells under conditions that mimic the hypoxic tumour microenvironment

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