Synergistic antitumor effect of MK-1775 and CUDC-907 against prostate cancer
Saisai Ma1,2, Yichen Xu1, Minmin Liu3
1School of Life Sciences, Jilin University, Changchun, China.
Abstract:
Due to the emergence of drug resistance, androgen receptor (AR)-targeted drugs still pose great challenges in the treatment of prostate cancer, and it is urgent to explore an innovative therapeutic strategy. MK-1775, a highly selective WEE1 inhibitor, is shown to have favorable therapeutic benefits in several solid tumor models. Recent evidence suggests that the combination of MK-1775 with DNA-damaging agents could lead to enhanced antitumor efficacy. Here, our results demonstrate that MK-1775 alone could indeed inhibit proliferation and induce apoptosis in prostate cancer. Moreover, the combination of MK-1775 and a dual PI3K and HDAC inhibitor, CUDC-907, can synergistically inhibit cell proliferation and dramatically induces apoptosis in prostate cancer cells. This effect is partially mediated by DNA damage, resulting from the downregulation of DNA damage response (DDR) proteins such as CDK, CHK, and RRM1/2. Notably, the combination of MK-1775 and CUDC-907 leads to significant antitumor effects in vivo. Our findings provide a strong basis for a promising combination strategy against prostate cancer.
Insights
MK-1775, a WEE1 inhibitor, shows promise in prostate cancer treatment. Combining it with CUDC-907 synergistically inhibits cancer cell growth and induces apoptosis, offering a novel therapeutic strategy.
Area of Science:
- Oncology
- Cancer Therapeutics
- Molecular Biology
Background:
- Androgen receptor (AR)-targeted therapies face challenges due to drug resistance in prostate cancer treatment.
- There is an urgent need for innovative therapeutic strategies to overcome treatment resistance.
- MK-1775, a WEE1 inhibitor, has demonstrated therapeutic benefits in various solid tumors.
Purpose of the Study:
- To investigate the efficacy of MK-1775 alone and in combination with CUDC-907 in prostate cancer.
- To elucidate the mechanisms underlying the combined therapeutic effect.
- To evaluate the in vivo antitumor activity of the MK-1775 and CUDC-907 combination.
Main Methods:
- In vitro proliferation and apoptosis assays in prostate cancer cell lines.
- Western blot analysis to assess DNA damage response (DDR) protein levels.
- In vivo studies to evaluate the antitumor effects of the drug combination.
Main Results:
- MK-1775 alone inhibited prostate cancer cell proliferation and induced apoptosis.
- The combination of MK-1775 and CUDC-907 synergistically inhibited cell proliferation and dramatically induced apoptosis.
- The combination therapy led to downregulation of DDR proteins (CDK, CHK, RRM1/2), indicating DNA damage.
- Significant antitumor effects were observed in vivo with the combined treatment.
Conclusions:
- MK-1775 demonstrates single-agent activity against prostate cancer.
- The combination of MK-1775 and CUDC-907 exhibits synergistic antitumor effects.
- This combination strategy, mediated by DNA damage and DDR inhibition, shows promise for prostate cancer treatment.
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