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Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer.

ABSTRACT: Pancreatic cancer remains a clinical challenge, thus new therapies are urgently needed. The selective Wee1 inhibitor MK-1775 has demonstrated promising results when combined with DNA damaging agents, and more recently with CHK1 inhibitors in various malignancies. We have previously demonstrated that treatment with the pan-histone deacetylase inhibitor panobinostat (LBH589) can cause down-regulation of CHK1. Accordingly, we investigated using panobinostat to down-regulate CHK1 in combination with MK-1775 to enhance cell death in preclinical pancreatic cancer models. We demonstrate that MK-1775 treatment results in increased H2AX phosphorylation, indicating increased DNA double-strand breaks, and activation of CHK1, which are both dependent on CDK activity. Combination of MK-1775 and panobinostat resulted in synergistic antitumor activity in six pancreatic cancer cell lines. Finally, our in vivo study using a pancreatic xenograft model reveals promising cooperative antitumor activity between MK-1775 and panobinostat. Our study provides compelling evidence that the combination of MK-1775 and panobinostat has antitumor activity in preclinical models of pancreatic cancer and supports the clinical development of panobinostat in combination with MK-1775 for the treatment of this deadly disease.

SUBMITTER: Wang G

PROVIDER: S-EPMC4282784 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer.

Wang Guan G Niu Xiaojia X Zhang Wenbo W Caldwell J Timothy JT Edwards Holly H Chen Wei W Taub Jeffrey W JW Zhao Lijing L Ge Yubin Y

Cancer letters 20141018 2 Pt B

Pancreatic cancer remains a clinical challenge, thus new therapies are urgently needed. The selective Wee1 inhibitor MK-1775 has demonstrated promising results when combined with DNA damaging agents, and more recently with CHK1 inhibitors in various malignancies. We have previously demonstrated that treatment with the pan-histone deacetylase inhibitor panobinostat (LBH589) can cause down-regulation of CHK1. Accordingly, we investigated using panobinostat to down-regulate CHK1 in combination with ...[more]

PMID: 25458954

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Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer.

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Synergistic antitumor interactions between MK-1775 and panobinostat in preclinical models of pancreatic cancer.

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