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. 2018 Nov 9;10:1758835918808509. doi: 10.1177/1758835918808509

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© The Author(s), 2018

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

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Figure 2. — CDK4/6, PARP and PI3K pathways inhibition by SMIs.

(a) Inhibition of CDK4/6 by SMIs (e.g. palbociclib, ribociclib and abemaciclib) through interaction with CDK4/6 and cyclin D1 activities are inhibited and hence suppressing phosphorylation of Rb, where E2F remains bound as an inactive complex and unable to activate the expression of genes that favor cell cycle progression. (b) The single-strand break in DNA recruits the PARP enzyme for DNA repair, and failure in repair can result in double-strand breaks during DNA replication. Thus, PARP inhibition by SMIs (e.g. olaparib, veliparib and talazoparib) induces DNA damage (cell death) through synthetic lethality with BRCA1/2-mutated breast cancer cells. (c) Inhibition of the PI3K pathway by SMIs (e.g. buparlisib and alpelisib) blocks the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) and inhibits its conversion into phosphatidylinositol (3,4,5)-trisphosphate (PIP₃), hindering the outcomes of the AKT pathway in protein synthesis and cell growth.

Key: direct positive regulation; indirect positive regulation; direct inhibition; inhibited regulation.

CDK4/6, cyclin-dependent kinase 4 and 6; PARP, poly (adenosine diphosphate-ribose) polymerase; PI3K, phosphoinositide 3-kinase; SMI, small molecule inhibitor.

Inline graphic — CDK4/6, PARP and PI3K pathways inhibition by SMIs.

(a) Inhibition of CDK4/6 by SMIs (e.g. palbociclib, ribociclib and abemaciclib) through interaction with CDK4/6 and cyclin D1 activities are inhibited and hence suppressing phosphorylation of Rb, where E2F remains bound as an inactive complex and unable to activate the expression of genes that favor cell cycle progression. (b) The single-strand break in DNA recruits the PARP enzyme for DNA repair, and failure in repair can result in double-strand breaks during DNA replication. Thus, PARP inhibition by SMIs (e.g. olaparib, veliparib and talazoparib) induces DNA damage (cell death) through synthetic lethality with BRCA1/2-mutated breast cancer cells. (c) Inhibition of the PI3K pathway by SMIs (e.g. buparlisib and alpelisib) blocks the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) and inhibits its conversion into phosphatidylinositol (3,4,5)-trisphosphate (PIP₃), hindering the outcomes of the AKT pathway in protein synthesis and cell growth.

Key: direct positive regulation; indirect positive regulation; direct inhibition; inhibited regulation.

CDK4/6, cyclin-dependent kinase 4 and 6; PARP, poly (adenosine diphosphate-ribose) polymerase; PI3K, phosphoinositide 3-kinase; SMI, small molecule inhibitor.