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Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia.

Blunt MD, Steele AJ - Leuk Res Rep (2015)

Bottom Line: However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy.The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses.This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms.

View Article: PubMed Central - PubMed

Affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO16 6YD, United Kingdom.

ABSTRACT
PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms.

No MeSH data available.


Related in: MedlinePlus

Schematic representation of the PI3K/mTOR signalling pathway with pharmacological agents in pre-clinical/clinical development for CLL indicated. (A) PI3K activation by receptor ligation induces re-localisation and activation of AKT (amongst other proteins not shown) which in turn initiates downstream signalling events crucial for CLL survival and proliferation. PI3K inhibitors in pre-clinical development, clinical trials or approved for CLL treatment are indicted. mTOR exists in two complexes; mTORC1 which phosphorylates S6 kinase and 4E-BP1 (eukaryotic translation initiation factor 4E-binding proteins) thereby promoting translation and protein synthesis and mTORC2 which phosphorylates and thus enhances the activation of AKT. (B) S6 kinase is activated downstream of PI3K and mTORC1 and promotes ribosomal translational activity. S6 kinase also acts in a negative feedback loop to constrain further PI3K mediated signalling. Selective inhibition of mTORC1 (for example by everolimus as indicated) abrogates S6 kinase mediated negative feedback mechanisms and leads to enhancement of PI3K mediated signalling and AKT activation. This effect is thought to have limited the efficacy of mTOR inhibitors alone in the clinic for various cancers. Use of a dual PI3K/mTOR inhibitor (for example PF-04691502 as indicated) prevents this amplification of PI3K signalling by preventing the phosphorylation of AKT by mTORC2 and by directly inhibiting PI3K.
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f0005: Schematic representation of the PI3K/mTOR signalling pathway with pharmacological agents in pre-clinical/clinical development for CLL indicated. (A) PI3K activation by receptor ligation induces re-localisation and activation of AKT (amongst other proteins not shown) which in turn initiates downstream signalling events crucial for CLL survival and proliferation. PI3K inhibitors in pre-clinical development, clinical trials or approved for CLL treatment are indicted. mTOR exists in two complexes; mTORC1 which phosphorylates S6 kinase and 4E-BP1 (eukaryotic translation initiation factor 4E-binding proteins) thereby promoting translation and protein synthesis and mTORC2 which phosphorylates and thus enhances the activation of AKT. (B) S6 kinase is activated downstream of PI3K and mTORC1 and promotes ribosomal translational activity. S6 kinase also acts in a negative feedback loop to constrain further PI3K mediated signalling. Selective inhibition of mTORC1 (for example by everolimus as indicated) abrogates S6 kinase mediated negative feedback mechanisms and leads to enhancement of PI3K mediated signalling and AKT activation. This effect is thought to have limited the efficacy of mTOR inhibitors alone in the clinic for various cancers. Use of a dual PI3K/mTOR inhibitor (for example PF-04691502 as indicated) prevents this amplification of PI3K signalling by preventing the phosphorylation of AKT by mTORC2 and by directly inhibiting PI3K.

Mentions: The crucial role of PI3Kδ in normal B cell biology was identified using genetic and pharmacological studies [4] and its haematopoietic restricted expression has made it an attractive target for therapeutic intervention in haematological malignancies (Fig. 1A).


Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia.

Blunt MD, Steele AJ - Leuk Res Rep (2015)

Schematic representation of the PI3K/mTOR signalling pathway with pharmacological agents in pre-clinical/clinical development for CLL indicated. (A) PI3K activation by receptor ligation induces re-localisation and activation of AKT (amongst other proteins not shown) which in turn initiates downstream signalling events crucial for CLL survival and proliferation. PI3K inhibitors in pre-clinical development, clinical trials or approved for CLL treatment are indicted. mTOR exists in two complexes; mTORC1 which phosphorylates S6 kinase and 4E-BP1 (eukaryotic translation initiation factor 4E-binding proteins) thereby promoting translation and protein synthesis and mTORC2 which phosphorylates and thus enhances the activation of AKT. (B) S6 kinase is activated downstream of PI3K and mTORC1 and promotes ribosomal translational activity. S6 kinase also acts in a negative feedback loop to constrain further PI3K mediated signalling. Selective inhibition of mTORC1 (for example by everolimus as indicated) abrogates S6 kinase mediated negative feedback mechanisms and leads to enhancement of PI3K mediated signalling and AKT activation. This effect is thought to have limited the efficacy of mTOR inhibitors alone in the clinic for various cancers. Use of a dual PI3K/mTOR inhibitor (for example PF-04691502 as indicated) prevents this amplification of PI3K signalling by preventing the phosphorylation of AKT by mTORC2 and by directly inhibiting PI3K.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4588368&req=5

f0005: Schematic representation of the PI3K/mTOR signalling pathway with pharmacological agents in pre-clinical/clinical development for CLL indicated. (A) PI3K activation by receptor ligation induces re-localisation and activation of AKT (amongst other proteins not shown) which in turn initiates downstream signalling events crucial for CLL survival and proliferation. PI3K inhibitors in pre-clinical development, clinical trials or approved for CLL treatment are indicted. mTOR exists in two complexes; mTORC1 which phosphorylates S6 kinase and 4E-BP1 (eukaryotic translation initiation factor 4E-binding proteins) thereby promoting translation and protein synthesis and mTORC2 which phosphorylates and thus enhances the activation of AKT. (B) S6 kinase is activated downstream of PI3K and mTORC1 and promotes ribosomal translational activity. S6 kinase also acts in a negative feedback loop to constrain further PI3K mediated signalling. Selective inhibition of mTORC1 (for example by everolimus as indicated) abrogates S6 kinase mediated negative feedback mechanisms and leads to enhancement of PI3K mediated signalling and AKT activation. This effect is thought to have limited the efficacy of mTOR inhibitors alone in the clinic for various cancers. Use of a dual PI3K/mTOR inhibitor (for example PF-04691502 as indicated) prevents this amplification of PI3K signalling by preventing the phosphorylation of AKT by mTORC2 and by directly inhibiting PI3K.
Mentions: The crucial role of PI3Kδ in normal B cell biology was identified using genetic and pharmacological studies [4] and its haematopoietic restricted expression has made it an attractive target for therapeutic intervention in haematological malignancies (Fig. 1A).

Bottom Line: However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy.The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses.This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms.

View Article: PubMed Central - PubMed

Affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, SO16 6YD, United Kingdom.

ABSTRACT
PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms.

No MeSH data available.


Related in: MedlinePlus