Inhibition of Pim-2 kinase by LT-171-861 promotes DNA damage and exhibits enhanced lethal effects with PARP inhibitor in multiple myeloma

Zhao, Cen; Yang, Dawei; Ye, Yuchen; Chen, Zhenzhong; Sun, Tifan; Zhao, Jing; Zhao, Kai; Lu, Na

doi:10.1016/j.bcp.2021.114648

Cited by 6 publications

(5 citation statements)

References 31 publications

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“…Several previous studies have investigated the roles of PIM2 kinase in MM cells 11,25,[28][29][30] , and other immune cells 17 ; however, few studies have elucidated the relationships between PIM2 kinase and NK cells. Here, we found that targeting PIM2 kinase inhibition can activate NK cells by regulating TIGIT function and expression in NK cells.…”

Section: Discussionmentioning

confidence: 99%

PIM2 Kinase Regulates TIGIT Expression and Function in NK Cells from Multiple Myeloma Patients

Fu,

Liu,

Wang

et al. 2024

Preprint

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PIM2 kinase influences plasma cell generation and bone loss in multiple myeloma (MM), which is highly associated with tumor progression and is a potential therapeutic target. Although PIM2 kinase is essential for natural killer (NK) cell homeostasis and development, its role in NK cells function remains unclear.Here,the expression of PIM2 kinase was reanalyzed in NK cells from MM patients and healthy donors using single-cell RNA sequencing (RNA-seq). The effect of PIM2 kinase on NK cell immune checkpoints and function were analyzed in NK cell and MM cell co-culture system. Mechanistically, The regulation of PIM2 kinase on TIGIT expression on NK cell was explored through NCBI, UCSC, JASPAR, GEPIA databases and ETS-1 knockdown in NK-92 cells.For further clinical application,PIM2 kinase inhibitors were screened in 160 natural flavonoids through kinase functional assays (ADP-Glo).Our findings reveal that PIM2 kinase was highly expressed in NK cells from MM patients and PIM2 kinase inhibitor increased NK cell function and downregulated TIGIT expression. Mechanistically, the PIM2 kinase inhibitor down-regulated TIGIT expression by reducing transcription factor ETS-1, which binds directly to the TIGIT promoter. For pre-clinical translational application, we screened two natural flavonoids kaempferol and quercetin dihydrate, which show higher efficacy in inhibiting PIM2 kinase. Subsequent co-culture system results demonstrated that kaempferol and quercetin dihydrate can decrease TIGIT expression and improved the anti-myeloma function in NK cells.All the above results confirm PIM2 kinase regulates TIGIT expression and function in NK cells from MM patients.PIM2 kinase inhibitor play a vital role in MM therapy.

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Section: Discussionmentioning

confidence: 99%

PIM2 Kinase Regulates TIGIT Expression and Function in NK Cells from Multiple Myeloma Patients

Fu,

Liu,

Wang

et al. 2024

Preprint

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“…LT‐171‐861, which can inhibit multiple kinases, including pim‐2, suppressed the proliferation and mediated the death of MM cells. A decline in phosphorylation products, such as 4EBP1 and BAD, was also observed, suggesting a correlation with the above process 43 . Pim‐2 has shown to inhibit the activation of the DNA damage response (DDR) pathway through ATR regulation.…”

Section: Pim Kinase In MMmentioning

confidence: 91%

“… 42 LT‐171‐861, a multiple kinase inhibitor that inhibits pim kinase, decreases CDK1 expression and increases CDK1 phosphorylation, inducing G2/M arrest in U266 and RPMI8226 cells. 43 Moreover, pim447 blocks the myeloma cell cycle at the G1‐to‐S transition by downregulating cyclin D2 and E1, which may be owing to the reduction of c‐Myc levels. 29 …”

Section: Pim Kinase In MMmentioning

confidence: 99%

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An overview of pim kinase as a target in multiple myeloma

et al. 2023

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Multiple myeloma (MM) is the second common hematologic malignancy manifesting as a clonal proliferation of plasma cells in the bone marrow. In recent years, high expression and activity of pim kinase have been found to be associated with both the progression and prognosis of a significant proportion of malignant diseases. Therefore, pim kinase has become a potential therapeutic target in the treatment of MM and some pim kinase inhibitors have demonstrated good efficacy in clinical trials. Based on nearly the entire literature searched from PubMed in the field of pim kinase in MM, the paper concluded how pim kinase got involved in the proliferation of myeloma cells, the progression of bone disease infiltration, and even in the regulation of the immune microenvironment. Next as a very promising drug, the effectiveness of pim kinase inhibitors as single agents or in combination with other drugs in the treatment of MM was also summarized. Our analysis will guide the clinical use of pim kinase inhibitors for managing tumor load and bone disease in MM patients.

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“…Also, PIM-2, a serine/threonine kinase that interacts with DDR and plays a critical role in promoting cell survival and preventing apoptosis, is commonly found upregulated in MM [51,52]. Another study has shown that LT-171-861, a synthetic new PIM-2 inhibitor, induced DNA damage by inhibiting HR/R pathway, activated apoptosis in MM cells and suppressed tumor growth in MM xenograft models [53]. Moreover, the PARP inhibitor olaparib could amplify the anticancer effect of LT-171-861 by reducing the growth of tumors in MM xenografted nude mice.…”

Section: The Ddr Network In the Outcome Of Anti-myeloma Therapymentioning

confidence: 99%

The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma

Malamos,

Papanikolaou,

Gavriatopoulou

et al. 2024

Preprint

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The DNA Damage Response (DDR) network and the mitogen-activated protein kinase (MAPK) signaling pathway are crucial mechanisms for the survival of all living beings. An accumulating body of evidence suggests that there is a crosstalk between these two systems, thus favoring the appropriate functioning of multi-cellular organisms. On the other hand, aberrations within these mechanisms are thought to play a vital role in the onset and progression of several diseases, including cancer, as well as in the emergence of drug resistance. Here, we provide an overview of the current knowledge regarding alterations in the DDR machinery and the MAPK signaling pathway, as well as abnormalities in the DDR-MAPK functional crosstalk in multiple myeloma, the second most common hematologic malignancy. We also present the latest advances in the development of anti-myeloma drugs targeting crucial DDR- and MAPK-associated molecular components. These data could potentially be exploited to discover new therapeutic targets and effective biomarkers, as well as for the design of novel clinical trials. Interestingly, they might provide a new approach to increase the efficacy of anti-myeloma therapy by combining drugs targeting the DDR network and the MAPK signaling pathway.

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Inhibition of Pim-2 kinase by LT-171-861 promotes DNA damage and exhibits enhanced lethal effects with PARP inhibitor in multiple myeloma

Cited by 6 publications

References 31 publications

PIM2 Kinase Regulates TIGIT Expression and Function in NK Cells from Multiple Myeloma Patients

PIM2 Kinase Regulates TIGIT Expression and Function in NK Cells from Multiple Myeloma Patients

An overview of pim kinase as a target in multiple myeloma

The Interplay between the DNA Damage Response (DDR) Network and the Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway in Multiple Myeloma

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