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Oncotarget: PIM and CDK4/6 suppresses both mTOR signaling and Rb phosphorylation


Oncotarget Volume 11, Issue 17 reported that aberrant activation of mitogenic signaling pathways in cancer promotes growth and proliferation of cells by activating mTOR and S6 phosphorylation, and D-cyclin kinases and Rb phosphorylation, respectively.

In this study, the authors showed that the CDK4/6 inhibitor abemaciclib inhibits PIM kinase and S6 phosphorylation in cancer cells and concurrent inhibition of PIM, CDK4, and CDK6 suppresses both S6 and Rb phosphorylation.

Dr. Sean G. Buchanan from Eli Lilly and Company in Indianapolis Indiana USA said, "Cyclin-dependent kinases (CDK) 4 and 6, which phosphorylate the retinoblastoma tumor suppressor protein Rb to promote G1 to S transition, are commonly dysregulated in cancer."

"Cyclin-dependent kinases (CDK) 4 and 6, which phosphorylate the retinoblastoma tumor suppressor protein Rb to promote G1 to S transition, are commonly dysregulated in cancer."

- Dr. Sean G. Buchanan, Eli Lilly and Company

In addition to stimulating cell cycle initiation via D-cyclin dependent kinases and Rb phosphorylation, these signaling pathways promote cell growth via mTOR activation and S6 phosphorylation, and it has been shown that inhibition of phosphorylation of both Rb and S6 is required for robust anti-tumor efficacy of drugs that inhibit cell signaling.

The approved CDK4/6 inhibitors show activity against additional kinases in vitro assays, but, for these additional targets of the drugs, direct evidence of inhibition in cells is limited, and in most cases it is unlikely that they are potently inhibited in cells at the plasma concentrations achieved at clinical doses.

Figure 1: Abemaciclib inhibits S6 phosphorylation independent of effects on CDK4/6 and Rb. (A) DMS-53 and MDA-MB-175 cells were treated with the indicated concentrations of abemaciclib, palbociclib, or ribociclib for 4 h and analyzed by western blot. (B) Mice bearing A549 xenograft tumors were treated with a single dose of abemaciclib or palbociclib (50 mg/kg). Tumors were collected 24 h post-treatment and analyzed by western blot. Plots indicate mean ± SEM (n = 5/group), relative to vehicle control. *p < 0.05; **p < 0.01; ***p < 0.001. (C) DMS-53 parental or RB1 KO cells were treated with the indicated concentrations of abemaciclib for 4 or 24 h and analyzed by western blot. (D) DMS-53 cells were transfected with CDK4, CDK6, CDK4+CDK6, or non-targeting control (NT) siRNA for 48 h and analyzed by western blot.

Here the authors show that abemaciclib can suppress the kinase activity of the oncoprotein PIM, and that, similar to PIM inhibitors, abemaciclib inhibits S6 phosphorylation in cells with wild-type PIK3CA and TSC2.

Their results suggest that abemaciclib can inhibit the mTOR pathway independently of its effects on Rb and support combining abemaciclib with PI3K/mTOR pathway inhibitors to fully suppress phosphorylation of S6 via multiple inputs.

The Buchanan Research Team concluded in their @Oncotarget Research Paper that combinations of CDK4/6 inhibitors with PI3K/mTOR pathway inhibitors are at various stages of clinical testing, including abemaciclib with PI3K/mTOR inhibitor LY3023414 or everolimus; palbociclib with PI3K/mTOR inhibitor PF-05212384, PI3K inhibitors GDC-0077, taselisib, or pictilisib, or everolimus; and ribociclib with PI3K inhibitors alpelisib or buparlisib, or everolimus.

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DOI - https://doi.org/10.18632/oncotarget.27539

Full text - https://www.oncotarget.com/article/27539/text/

Correspondence to - Sean G. Buchanan - buchananse@lilly.com

Keywords - abemaciclib, CDK4/6, PIM, mTOR, S6

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