Control of translational activation by PIM kinase in activated B-cell diffuse large B-cell lymphoma confers sensitivity to inhibition by PIM447

Peters, Tara L.; Li, Lingxiao; Tula-Sanchez, Ana A.; Pongtornpipat, Praechompoo; Schatz, Jonathan H.

doi:10.18632/oncotarget.11457

Cited by 18 publications

(21 citation statements)

References 60 publications

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“…We also examined the cytotoxic assay with other commercially available PIM inhibitors. AZD1208 (Dakin et al , ; Keeton et al , ; Harada et al , ) is another member of the thiazolidine‐2,4‐dione‐family compounds; and CX‐6258 (Haddach et al , ) and PIM447 (Peters et al , ) are structurally different types of PIM inhibitors. AZD1208, CX‐6258 and PIM447 also induced dose‐dependent MM cell death at pH 7·4 (Fig C).…”

Section: Resultsmentioning

confidence: 99%

Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity

et al. 2018

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Proviral Integrations of Moloney virus 2 (PIM2) is overexpressed in multiple myeloma (MM) cells, and regarded as an important therapeutic target. Here, we aimed to validate the therapeutic efficacy of different types of PIM inhibitors against MM cells for their possible clinical application. Intriguingly, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a reduced PIM2 protein levels and impaired MM cell survival preferentially in acidic conditions, in contrast to other types of PIM inhibitors, including AZD1208, CX-6258 and PIM447. SMI-16a also suppressed the drug efflux function of breast cancer resistance protein, minimized the sizes of side populations and reduced in vitro colony-forming capacity and in vivo tumourigenic activity in MM cells, suggesting impairment of their clonogenic capacity. PIM2 is known to be subject to ubiquitination-independent proteasomal degradation. Consistent with this, the proteasome inhibitors bortezomib and carfilzomib increased PIM2 protein levels in MM cells without affecting its mRNA levels. However, SMI-16a mitigated the PIM2 protein increase and cooperatively enhanced anti-MM effects in combination with carfilzomib. Collectively, the thiazolidine-2,4-dione-family compounds SMI-16a and SMI-4a uniquely reduce PIM2 protein in MM cells, which may contribute to their profound efficacy in addition to their immediate kinase inhibition. Their combination with proteasome inhibitors is envisioned.

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Section: Resultsmentioning

confidence: 99%

Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity

et al. 2018

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“…One of these mutations (p.H68Y) has been previously reported to increase the activity of the enzyme, compared to the wild-type [ 20 ]. Others such as those in aa L184, L182, S146 and P125, previously described [ 21 ], have been shown not to affect the catalytic activity of the protein. The importance of PIM1 in the development and evolution of hematologic malignancies, especially in lymphomas, has been known for many years [ 11 , 22 – 23 ].…”

Section: Discussionmentioning

confidence: 99%

Mutational profile of primary breast diffuse large B-cell lymphoma

et al. 2017

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Primary breast lymphoma is a rare form of extra-nodal lymphoid neoplasm. The most common histological type is the diffuse large B-cell lymphoma, which represents 60–80% of all the cases. Our study analyzes the mutational profile of the primary lymphoma of the breast through targeted massive sequencing with a panel of 38 genes in a group of 17 patients with primary breast diffuse large B-cell lymphoma. Seventy-point-five percent of the patients presented with stage IE and 29.5% with stage IIE. 44% of the cases correspond to lymphomas with germinal center phenotype and 33.3% to activated B-cell. The genes with a higher mutational frequency include PIM1 (in 50% of the analyzed samples), MYD88 (39%), CD79B, PRDM1 and CARD11 (17%), KMT2D, TNFIAP3 and CREBBP (11%). The profile of mutant genes involves mostly the NFκB signaling pathway. The high frequency of mutations in PIM1 compared with other lymphomas may have implications in the clinical presentation and evolution of this type of lymphoma.

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“…55 PIM447 is a selective small molecule pan-PIM inhibitor that has not yet been investigated in PCa; however, the results in large B-cell lymphoma suggest that PIM inhibition by this drug leads to inactivation of the mTORC1 signaling complex, followed by the inactivation of capdependent protein translation, thereby leading to apoptosis and cell death. 56 This suggests that the known interactions between PIM and PI3K signaling could offer broad signaling effects in response to PIM inhibition as a monotherapy.…”

Section: Pim Inhibition As a Monotherapymentioning

confidence: 99%

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

Luszczak

Kumar

Sathyadevan

et al. 2020

Sig Transduct Target Ther

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PIM kinases have been shown to play a role in prostate cancer development and progression, as well as in some of the hallmarks of cancer, especially proliferation and apoptosis. Their upregulation in prostate cancer has been correlated with decreased patient overall survival and therapy resistance. Initial efforts to inhibit PIM with monotherapies have been hampered by compensatory upregulation of other pathways and drug toxicity, and as such, it has been suggested that co-targeting PIM with other treatment approaches may permit lower doses and be a more viable option in the clinic. Here, we present the rationale and basis for cotargeting PIM with inhibitors of PI3K/mTOR/AKT, JAK/STAT, MYC, stemness, and RNA Polymerase I transcription, along with other therapies, including androgen deprivation, radiotherapy, chemotherapy, and immunotherapy. Such combined approaches could potentially be used as neoadjuvant therapies, limiting the development of resistance to treatments or sensitizing cells to other therapeutics. To determine which drugs should be combined with PIM inhibitors for each patient, it will be key to develop companion diagnostics that predict response to each co-targeted option, hopefully providing a personalized medicine pathway for subsets of prostate cancer patients in the future.

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Control of translational activation by PIM kinase in activated B-cell diffuse large B-cell lymphoma confers sensitivity to inhibition by PIM447

Cited by 18 publications

References 60 publications

Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity

Unique anti‐myeloma activity by thiazolidine‐2,4‐dione compounds with Pim inhibiting activity

Mutational profile of primary breast diffuse large B-cell lymphoma

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

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