Contributions
Abstract: EP865
Type: E-Poster Presentation
Session title: Lymphoma Biology & Translational Research
Background
Polo-like kinase 4 (PLK4) has been suggested as a tumor promoter role in solid malignancies. Elevated PLK4 expression was associated with progressed grade, inferior survival and reduced chemosensitivity, highlighting as an adverse prognosis indicator and a potential target for cancer therapy. CFI-400945 was the first orally available potent PLK4 inhibitor. The antineoplastic effects of CFI-400945 have been reported in many cancers and this inhibitor has entered phase Ⅰ/Ⅱ clinical trials in advanced solid tumors. However, the role of PLK4 in DLBCL is still unclear. Whether CFI-400945 has therapeutic potential in DLBCL remained undefined.
Aims
We aim to investigate the biological role of PLK4 and the antitumor effects of CFI-400945 in DLBCL.
Methods
Analysis of public database and clinical specimens was used to validate PLK4 expression and evaluate its clinical significance. Cell proliferation and apoptosis was assessed by CCK8 and flow cytometry analysis. Knockdown of PLK4 with shRNA was used to evaluate the effect of PLK4 expression on CFI-400945 potency. The effectiveness of the CFI-400945 as a single agent and in combination with doxorubicin in DLBCL cells was evaluated in vitro and in vivo studies.
Results
PLK4 expression was up-regulated at both transcriptional and translational levels in DLBCL cells. High levels of PLK4 expression predicted inferior prognosis in the patients receiving CHOP-based treatment. We then evaluated the antitumor effects of PLK4 inhibition by CFI-400945. The results demonstrated that treatment of PLK4 inhibitor induced a decrease in cell proliferation, an increase in cell apoptosis and a block at the G2-M transition in a dose-dependent manner. Furthermore, we found that the antineoplastic effects of CFI-400945 in DLBCL cell lines were due to the increased DNA damage, as observed by increased accumulation of γH2AX through phosphorylation of CHK1/CHK2. Since PLK4 inhibition affects DNA damage, we next aimed to explore the effects of PLK4 expression on sensitivity of DNA damage-inducing drugs (e.g., doxorubicin). Knockdown of PLK4 improved the anti-tumor effects of doxorubicin in DLBCL cells. PLK4 inhibition resulted in increased doxorubicin-induced DNA damage. Moreover, a combined treatment of CFI-400945 and doxorubicin was associated with promising antiproliferative effects in DLBCL cells. We then investigated the synergistic anti-tumor effects of the combined treatment in vivo. Mice treated with CFI-400945 and doxorubicin had significantly lower tumor burden after 21 days compared with those treated with vehicle or doxorubicin alone.
Conclusion
The present study suggests that PLK4 is a potential therapeutic target of DLBCL. The levels of PLK4 may serve as a determinant of doxorubicin sensitivity and a predictive biomarker of the patients with DLBCL. Inhibition of PLK4 by CFI-400945 represents a promising strategy for DLBCL, with potential for combination treatment with doxorubicin-involved therapy.
Keyword(s): Diffuse large B cell lymphoma, DNA damage, Doxorubicin, Kinase inhibitor
Abstract: EP865
Type: E-Poster Presentation
Session title: Lymphoma Biology & Translational Research
Background
Polo-like kinase 4 (PLK4) has been suggested as a tumor promoter role in solid malignancies. Elevated PLK4 expression was associated with progressed grade, inferior survival and reduced chemosensitivity, highlighting as an adverse prognosis indicator and a potential target for cancer therapy. CFI-400945 was the first orally available potent PLK4 inhibitor. The antineoplastic effects of CFI-400945 have been reported in many cancers and this inhibitor has entered phase Ⅰ/Ⅱ clinical trials in advanced solid tumors. However, the role of PLK4 in DLBCL is still unclear. Whether CFI-400945 has therapeutic potential in DLBCL remained undefined.
Aims
We aim to investigate the biological role of PLK4 and the antitumor effects of CFI-400945 in DLBCL.
Methods
Analysis of public database and clinical specimens was used to validate PLK4 expression and evaluate its clinical significance. Cell proliferation and apoptosis was assessed by CCK8 and flow cytometry analysis. Knockdown of PLK4 with shRNA was used to evaluate the effect of PLK4 expression on CFI-400945 potency. The effectiveness of the CFI-400945 as a single agent and in combination with doxorubicin in DLBCL cells was evaluated in vitro and in vivo studies.
Results
PLK4 expression was up-regulated at both transcriptional and translational levels in DLBCL cells. High levels of PLK4 expression predicted inferior prognosis in the patients receiving CHOP-based treatment. We then evaluated the antitumor effects of PLK4 inhibition by CFI-400945. The results demonstrated that treatment of PLK4 inhibitor induced a decrease in cell proliferation, an increase in cell apoptosis and a block at the G2-M transition in a dose-dependent manner. Furthermore, we found that the antineoplastic effects of CFI-400945 in DLBCL cell lines were due to the increased DNA damage, as observed by increased accumulation of γH2AX through phosphorylation of CHK1/CHK2. Since PLK4 inhibition affects DNA damage, we next aimed to explore the effects of PLK4 expression on sensitivity of DNA damage-inducing drugs (e.g., doxorubicin). Knockdown of PLK4 improved the anti-tumor effects of doxorubicin in DLBCL cells. PLK4 inhibition resulted in increased doxorubicin-induced DNA damage. Moreover, a combined treatment of CFI-400945 and doxorubicin was associated with promising antiproliferative effects in DLBCL cells. We then investigated the synergistic anti-tumor effects of the combined treatment in vivo. Mice treated with CFI-400945 and doxorubicin had significantly lower tumor burden after 21 days compared with those treated with vehicle or doxorubicin alone.
Conclusion
The present study suggests that PLK4 is a potential therapeutic target of DLBCL. The levels of PLK4 may serve as a determinant of doxorubicin sensitivity and a predictive biomarker of the patients with DLBCL. Inhibition of PLK4 by CFI-400945 represents a promising strategy for DLBCL, with potential for combination treatment with doxorubicin-involved therapy.
Keyword(s): Diffuse large B cell lymphoma, DNA damage, Doxorubicin, Kinase inhibitor