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Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma.

ABSTRACT: Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that short-term treatment with the Chk1 inhibitor AZD7762 reduces metabolism in pembrolizumab tumors, synergizing with the DNA-damaging drug gemcitabine to reduce tumor size in these models. Our results offer preclinical proof of concept for use of a Chk1 inhibitor to safely enhance the efficacy of gemcitabine, particularly in aggressive KRAS-driven LKB1-deficient lung adenocarcinomas. Cancer Res; 77(18); 5068-76. ©2017 AACR.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5600859 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma.

Liu Yan Y Li Yuyang Y Wang Xiaoen X Liu Feiyang F Gao Peng P Quinn Max M MM Li Fei F Merlino Ashley A AA Benes Cyril C Liu Qingsong Q Gray Nathanael S NS Wong Kwok-Kin KK

Cancer research 20170728 18

Cells lacking the tumor suppressor gene LKB1/STK11 alter their metabolism to match the demands of accelerated growth, leaving them highly vulnerable to stress. However, targeted therapy for LKB1-deficient cancers has yet to be reported. In both Kras/p53/Lkb1 cell lines and a genetically engineered mouse model of Kras/p53/Lkb1-induced lung cancer, much higher rates of DNA damage occur, resulting in increased dependence on Chk1 checkpoint function. Here we demonstrate that sho ...[more]

PMID: 28754670

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Project description:BackgroundLung cancer (LC) is one of the leading causes of death worldwide, which highlights the urgent need for better therapies. Peroxisome proliferator-activated nuclear receptor alpha (PPAR?), known as a key nuclear transcription factor involved in glucose and lipid metabolism, has been also implicated in endothelial proliferation and angiogenesis. However, the effects and potential mechanisms of the novel PPAR? ligand, AVE8134, on LC growth and progression remain unclear.MethodsA subcutaneous tumour was established in mice by injecting TC-1 lung tumour cells (~?1?×?106 cells) into their shaved left flank. These mice were treated with three different PPAR? ligands: AVE8134 (0.025% in drinking water), Wyeth-14,643 (0.025%), or Bezafibrate (0.3%). Tumour sizes and metastasis between treated and untreated mice were then compared by morphology and histology, and the metabolites of arachidonic acid (AA) were detected by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Inhibition of either Cyp2c44 expression by genetic disruption or cyclooxygenase (COX) activity by indomethacin was used to test the mechanisms by which AVE8134 affects tumour growth.ResultsThe pharmacodynamics effects of AVE8134, Wyeth-14,643, and Bezafibrate on lipids control were similar. However, their effects on tumour suppression were different. Eicosanoid profile analysis showed that all PPAR? ligands reduced the production of AA-derived epoxyeicosatrienoic acids (EETs) and increased the hydroxyl product, 11-hydroxyeicosatetraenoic acids (11-HETE). Moreover, increased 11-HETE promoted endothelial proliferation, angiogenesis, and subsequent tumour deterioration in a dose-dependent manner possibly via activating the AKT/extracellular signal-regulated kinase (ERK) pathway. The increased 11-HETE partly neutralized the benefits provided by the Cyp2c44-EETs system inhibited by PPAR? ligands in tumour-bearing mice. AVE8134 treatment worsened the tumour phenotype in Cyp2c44 knockout mice, indicating that AVE8134 has contradictory effects on tumour growth. The COX inhibitor indomethacin strengthened the inhibitory actions of AVE8134 on tumour growth and metastasis by inhibiting the 11-HETE production in vivo and in vitro.ConclusionIn this study, we found that the degrees of inhibition on LC growth and metastasis by PPAR? ligands depended on their bidirectional regulation on EETs and 11-HETE. Considering their safety and efficacy, the novel PPAR? ligand, AVE8134, is a potentially ideal anti-angiogenesis drug for cancer treatment when jointly applied with the COX inhibitor indomethacin.

Dataset Information

Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma.

Publications

Gemcitabine and Chk1 Inhibitor AZD7762 Synergistically Suppress the Growth of Lkb1-Deficient Lung Adenocarcinoma.

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