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Inhibition of Rb and mTOR signaling associates with synergistic anticancer effect of palbociclib and erlotinib in glioblastoma cells

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Summary

Genomic studies have established a set of three core-signaling pathways, receptor tyrosine kinase (RTK), p53 and retinoblastoma (Rb) signaling pathways, contributing glioblastoma (GBM) and revealed that dysregulation of at least two pathways is required for GBM progression. In the present study, we investigate efficacy of combination of palbociclib, cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, and erlotinib, epidermal growth factor receptor (EGFR) inhibitor in GBM cell systems with different p53 status. Cell proliferation and colony formation assays showed that the combination treatment synergistically suppressed GBM cell proliferation. LN229 cells with mutant p53 and wild-type PTEN were more sensitive to the combination treatment. Further studies indicated that the synergetic anti-GBM effects were due to cell apoptosis induction and cell cycle arrest at G1 phase. Signaling examination indicated that levels of p-Rb and p-4E-BP1 significantly decreased by the combination treatment; however, Akt and MAPK signaling were differentially suppressed among the three GBM cell lines. Hence, our data demonstrate that palbociclib and erlotinib exert synergistic anti-GBM activity, providing pre-clinical evidence and a proof-ofconcept that usage of the combination of EGFR and CDK4/6 inhibitors for GBM treatment.

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Funding

This work is supported by grants from Natural Science Foundation of Hunan (No.2016jj3169 and 2015jj4101).

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  1. Songlin Liu and Yunhong Tang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

    Songlin Liu, Yunhong Tang, Xianrui Yuan, Dun Yuan, Junyu Liu, Buyan Li & Yifeng Li

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  1. Songlin Liu
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Correspondence to Yifeng Li.

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Supplemental figure 1

Effect of palbociclib, erlotinib alone or combination on cell cycle progression in LNZ308 (A), LN229 (B), and U87MG cells. Following treated with palbociclib (0.5 μM), erlotinib (2 μM) alone or combination for 24 h, cells were collected, fixed, and stained with PI as described followed by Flow cytometry analysis. (PDF 321 kb)

Supplemental figure 2

Effect of palbociclib, erlotinib alone or combination on expression levels of CDK4, CDK6, and Cyclin D1 proteins. Following treatment with palbociclib, erlotinib alone or combination at the concentration described in Fig. 4, cell lysates were collected and analyzed western blotting using indicated antibodies. (PDF 436 kb)

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Liu, S., Tang, Y., Yuan, X. et al. Inhibition of Rb and mTOR signaling associates with synergistic anticancer effect of palbociclib and erlotinib in glioblastoma cells. Invest New Drugs 36, 961–969 (2018). https://doi.org/10.1007/s10637-018-0575-z

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