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Targeting the Pim kinases in multiple myeloma.

Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M - Blood Cancer J (2015)

Bottom Line: A number of Pim inhibitors are now under development with lead compounds entering the clinic.The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM.It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

View Article: PubMed Central - PubMed

Affiliation: Apoptosis Research Centre, National University of Ireland Galway and Department of Haematology, Galway University Hospital, Galway, Ireland.

ABSTRACT
Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

No MeSH data available.


Related in: MedlinePlus

Pim signaling in MM. Pim-2 is upregulated in MM. BMSCs, present in the microenvironment secrete IL-6 (depicted in grey) and increase Pim-2 transcription via STAT3 signaling. OCs release tumor necrosis factor family members TNFα, BAFF and APRIL (depicted in green), which then act via NFκB to increase Pim-2 transcription. Pim-2 has a role in prevention of apoptosis by phosphorylating MDM2 and reducing the degradation of p53, phosphorylation of ASK-1 and phosphorylation of the pro-apoptotic BAD at serine 112. This latter effect on BAD is shared with the PI3K/AKT/mTOR pathway also important in MM. These two pathways also converge on mTOR signaling. Pim-2 phosphorylates TSC2 to release the inhibitory effect of Rheb on mTORC1. Akt phosphorylates PRAS40 to activate mTORC1. Downstream of mTOR activation, both cap-dependent and cap-independent translation is initiated. The ribosomal proteins 4EBP1 and S6 kinase are phosphorylated to initiate cap-independent translation. Following phosphorylation of 4EBP1, eIF4E is released and forms a translation initiation complex with eIF4A, eIF4G and eIF3. The ribosomal 40S subunit can then bind to ‘weak' mRNA transcripts which contain a GC-rich region and capped by 7-methylguanosine. Among the pro-myeloma proteins translated in this manner are MYC, cyclin D1, MCL-1 and the Pim kinases themselves. This forms part of the oncogenic collaboration between the Pims and MYC. The Pims cannot perform oncogenic functions in the absence of MYC expression,39 and in turn, the Pims phosphorylate and stabilize MYC.40 Pims complex with MYC and MAX and are recruited to the E-box of MYC where Pims phosphorylate serine10 of histone 3 (H3S10) to induce transcription of up to 20% of MYC target genes.41 A putative role for the Pim kinases in MM, as has been demonstrated in other hematologic malignancies, is phosphorylation of CXCR4 on serine 339 with resultant internalization and re-expression of CXCR4, facilitating homing and migration.
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fig2: Pim signaling in MM. Pim-2 is upregulated in MM. BMSCs, present in the microenvironment secrete IL-6 (depicted in grey) and increase Pim-2 transcription via STAT3 signaling. OCs release tumor necrosis factor family members TNFα, BAFF and APRIL (depicted in green), which then act via NFκB to increase Pim-2 transcription. Pim-2 has a role in prevention of apoptosis by phosphorylating MDM2 and reducing the degradation of p53, phosphorylation of ASK-1 and phosphorylation of the pro-apoptotic BAD at serine 112. This latter effect on BAD is shared with the PI3K/AKT/mTOR pathway also important in MM. These two pathways also converge on mTOR signaling. Pim-2 phosphorylates TSC2 to release the inhibitory effect of Rheb on mTORC1. Akt phosphorylates PRAS40 to activate mTORC1. Downstream of mTOR activation, both cap-dependent and cap-independent translation is initiated. The ribosomal proteins 4EBP1 and S6 kinase are phosphorylated to initiate cap-independent translation. Following phosphorylation of 4EBP1, eIF4E is released and forms a translation initiation complex with eIF4A, eIF4G and eIF3. The ribosomal 40S subunit can then bind to ‘weak' mRNA transcripts which contain a GC-rich region and capped by 7-methylguanosine. Among the pro-myeloma proteins translated in this manner are MYC, cyclin D1, MCL-1 and the Pim kinases themselves. This forms part of the oncogenic collaboration between the Pims and MYC. The Pims cannot perform oncogenic functions in the absence of MYC expression,39 and in turn, the Pims phosphorylate and stabilize MYC.40 Pims complex with MYC and MAX and are recruited to the E-box of MYC where Pims phosphorylate serine10 of histone 3 (H3S10) to induce transcription of up to 20% of MYC target genes.41 A putative role for the Pim kinases in MM, as has been demonstrated in other hematologic malignancies, is phosphorylation of CXCR4 on serine 339 with resultant internalization and re-expression of CXCR4, facilitating homing and migration.

Mentions: Pims recently emerged as an exciting new target in MM. High expression of Pim-2 is seen in MM and important in mediating MM cell survival and proliferation, by inhibiting apoptosis and inducing cap-dependent translation, respectively (Figure 2). Furthermore, with Myc dysregulation, the most frequent genetic abnormality encountered in MM,5 and strong oncogenic collaboration between the Pims and Myc, Pim inhibitors seem an obvious choice for drug development in MM. In addition, Pims crosstalk with and share significantly overlapping functions with other kinase signaling pathways active in MM.


Targeting the Pim kinases in multiple myeloma.

Keane NA, Reidy M, Natoni A, Raab MS, O'Dwyer M - Blood Cancer J (2015)

Pim signaling in MM. Pim-2 is upregulated in MM. BMSCs, present in the microenvironment secrete IL-6 (depicted in grey) and increase Pim-2 transcription via STAT3 signaling. OCs release tumor necrosis factor family members TNFα, BAFF and APRIL (depicted in green), which then act via NFκB to increase Pim-2 transcription. Pim-2 has a role in prevention of apoptosis by phosphorylating MDM2 and reducing the degradation of p53, phosphorylation of ASK-1 and phosphorylation of the pro-apoptotic BAD at serine 112. This latter effect on BAD is shared with the PI3K/AKT/mTOR pathway also important in MM. These two pathways also converge on mTOR signaling. Pim-2 phosphorylates TSC2 to release the inhibitory effect of Rheb on mTORC1. Akt phosphorylates PRAS40 to activate mTORC1. Downstream of mTOR activation, both cap-dependent and cap-independent translation is initiated. The ribosomal proteins 4EBP1 and S6 kinase are phosphorylated to initiate cap-independent translation. Following phosphorylation of 4EBP1, eIF4E is released and forms a translation initiation complex with eIF4A, eIF4G and eIF3. The ribosomal 40S subunit can then bind to ‘weak' mRNA transcripts which contain a GC-rich region and capped by 7-methylguanosine. Among the pro-myeloma proteins translated in this manner are MYC, cyclin D1, MCL-1 and the Pim kinases themselves. This forms part of the oncogenic collaboration between the Pims and MYC. The Pims cannot perform oncogenic functions in the absence of MYC expression,39 and in turn, the Pims phosphorylate and stabilize MYC.40 Pims complex with MYC and MAX and are recruited to the E-box of MYC where Pims phosphorylate serine10 of histone 3 (H3S10) to induce transcription of up to 20% of MYC target genes.41 A putative role for the Pim kinases in MM, as has been demonstrated in other hematologic malignancies, is phosphorylation of CXCR4 on serine 339 with resultant internalization and re-expression of CXCR4, facilitating homing and migration.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Pim signaling in MM. Pim-2 is upregulated in MM. BMSCs, present in the microenvironment secrete IL-6 (depicted in grey) and increase Pim-2 transcription via STAT3 signaling. OCs release tumor necrosis factor family members TNFα, BAFF and APRIL (depicted in green), which then act via NFκB to increase Pim-2 transcription. Pim-2 has a role in prevention of apoptosis by phosphorylating MDM2 and reducing the degradation of p53, phosphorylation of ASK-1 and phosphorylation of the pro-apoptotic BAD at serine 112. This latter effect on BAD is shared with the PI3K/AKT/mTOR pathway also important in MM. These two pathways also converge on mTOR signaling. Pim-2 phosphorylates TSC2 to release the inhibitory effect of Rheb on mTORC1. Akt phosphorylates PRAS40 to activate mTORC1. Downstream of mTOR activation, both cap-dependent and cap-independent translation is initiated. The ribosomal proteins 4EBP1 and S6 kinase are phosphorylated to initiate cap-independent translation. Following phosphorylation of 4EBP1, eIF4E is released and forms a translation initiation complex with eIF4A, eIF4G and eIF3. The ribosomal 40S subunit can then bind to ‘weak' mRNA transcripts which contain a GC-rich region and capped by 7-methylguanosine. Among the pro-myeloma proteins translated in this manner are MYC, cyclin D1, MCL-1 and the Pim kinases themselves. This forms part of the oncogenic collaboration between the Pims and MYC. The Pims cannot perform oncogenic functions in the absence of MYC expression,39 and in turn, the Pims phosphorylate and stabilize MYC.40 Pims complex with MYC and MAX and are recruited to the E-box of MYC where Pims phosphorylate serine10 of histone 3 (H3S10) to induce transcription of up to 20% of MYC target genes.41 A putative role for the Pim kinases in MM, as has been demonstrated in other hematologic malignancies, is phosphorylation of CXCR4 on serine 339 with resultant internalization and re-expression of CXCR4, facilitating homing and migration.
Mentions: Pims recently emerged as an exciting new target in MM. High expression of Pim-2 is seen in MM and important in mediating MM cell survival and proliferation, by inhibiting apoptosis and inducing cap-dependent translation, respectively (Figure 2). Furthermore, with Myc dysregulation, the most frequent genetic abnormality encountered in MM,5 and strong oncogenic collaboration between the Pims and Myc, Pim inhibitors seem an obvious choice for drug development in MM. In addition, Pims crosstalk with and share significantly overlapping functions with other kinase signaling pathways active in MM.

Bottom Line: A number of Pim inhibitors are now under development with lead compounds entering the clinic.The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM.It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

View Article: PubMed Central - PubMed

Affiliation: Apoptosis Research Centre, National University of Ireland Galway and Department of Haematology, Galway University Hospital, Galway, Ireland.

ABSTRACT
Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

No MeSH data available.


Related in: MedlinePlus