Checkpoint Kinase Inhibitor AZD7762 Overcomes Cisplatin Resistance in Clear Cell Carcinoma of the Ovary

Itamochi, Hiroaki; Nishimura, Masaharu; Oumi, Nao; Kato, Masatane; Oishi, Tsutomu; Shimada, Muneaki; Sato, Shinya; Naniwa, Jun; Sato, Seiya; Kudoh, Akiko; Kigawa, Junzo; Harada, Tasuku

doi:10.1097/igc.0000000000000014

Cited by 37 publications

(32 citation statements)

References 27 publications

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“…Hence, the current study provides a rationale for the testing of CHK1 inhibitors or other therapy strategies that interfere with CHK1 function in combination with gemcitabine in gemcitabine-naïve UC patients, in particular for patients with advanced and/or metastatic disease who are ineligible for cisplatin. Notably, potentiation of gemcitabine effects by AZD7762 in xenografts from several other cancer types has been already reported [14, 44, 45]. The next step towards application of our results in bladder cancer should therefore be determining the optimal combinations of gemcitabine and CHK1 inhibitors in animal models of the disease.…”

Section: Discussionmentioning

confidence: 60%

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Isono

Hoffmann

Pinkerneil

et al. 2017

J Exp Clin Cancer Res

127

111

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BackgroundMore effective chemotherapies are urgently needed for bladder cancer, a major cause of morbidity and mortality worldwide. We therefore explored the efficacy of the combination of gemcitabine and AZD7762, a checkpoint kinase 1/2 (CHK1/2) inhibitor, for bladder cancer.MethodsViability, clonogenicity, cell cycle distribution and apoptosis were assessed in urothelial cancer cell lines and various non-malignant urothelial cells treated with gemcitabine and AZD7762. DNA damage was assessed by γH2A.X and 53-BP1 staining and checkpoint activation was followed by Western blotting. Pharmacological inhibition of CHK1 and CHK2 was compared to downregulation of either CHK1 or CHK2 using siRNAs.ResultsCombined use of gemcitabine and AZD7762 synergistically reduced urothelial carcinoma cell viability and colony formation relative to either single treatment. Non-malignant urothelial cells were substantially less sensitive to this drug combination. Gemcitabine plus AZD7762 inhibited cell cycle progression causing cell accumulation in S-phase. Moreover, the combination induced pronounced levels of apoptosis as indicated by an increase in the fraction of sub-G1 cells, in the levels of cleaved PARP, and in caspase 3/7 activity. Mechanistic investigations showed that AZD7762 treatment inhibited the repair of gemcitabine-induced double strand breaks by interference with CHK1, since siRNA-mediated depletion of CHK1 but not of CHK2 mimicked the effects of AZD7762.ConclusionsAZD7762 enhanced sensitivity of urothelial carcinoma cells to gemcitabine by inhibiting DNA repair and disturbing checkpoints. Combining gemcitabine with CHK1 inhibition holds promise for urothelial cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-016-0473-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 60%

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Isono

Hoffmann

Pinkerneil

et al. 2017

J Exp Clin Cancer Res

127

111

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“…T, tumor, N, normal blood from the same patient (in 3 cases, paired normal breast tissues are shown as blood tissues are not available). Copy number data for index breast cancer cell lines and tumors are from Heiser et al 44 and TCGA 49 respectively. ( d ) The incidence of ESR1-CCDC170 fusion in different breast cancer clinical subtypes.…”

Section: Figurementioning

confidence: 99%

Recurrent ESR1–CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers

et al. 2014

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Characterizing the genetic alterations leading to the more aggressive forms of estrogen receptor positive (ER+) breast cancers are of critical significance in breast cancer management. Here we identify recurrent rearrangements between estrogen receptor gene ESR1 and its neighbor CCDC170, which are enriched in the more aggressive and endocrine-resistant luminal-B tumors, through large-scale analyses of breast cancer transcriptome and copy number alterations. Further screening of 200 ER+ breast cancers identifies eight ESR1-CCDC170 positive tumors. These fusions encode N-terminally truncated CCDC170 proteins (ΔCCDC170). When introduced into ER+ breast cancer cells, ΔCCDC170 leads to markedly increased cell motility and anchorage-independent growth, reduced endocrine sensitivity, and enhanced xenograft tumor formation. Mechanistic studies suggest that ΔCCDC170 engages Gab1 signalosome to potentiate growth factor signaling and enhance cell motility. Together, this study identifies neoplastic ESR1-CCDC170 fusions in a more aggressive subset of ER+ breast cancer, which suggests a new concept of ER pathobiology in breast cancer.

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“…Whether targeting of Chk is equally effective in epithelial and mesenchymal-like UC cells remains to be elucidated in forthcoming studies. Noteworthy, Chk inhibition was reported to overcome CisPt resistance of head and neck cancer cells [41] as well as of clear cell carcinoma of the ovary [42] in vitro , supporting the hypothesis that targeting of Chk might be a useful approach to deal with acquired CisPt resistance of different types of tumor cells. Taken together, our data support the current view that increasing replicative stress in tumor cells might be a promising therapeutic strategy also in UC [29].…”

Section: Resultsmentioning

confidence: 87%

Distinct mechanisms contribute to acquired cisplatin resistance of urothelial carcinoma cells

et al. 2016

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Cisplatin (CisPt) is frequently used in the therapy of urothelial carcinoma (UC). Its therapeutic efficacy is limited by inherent or acquired drug resistance. Here, we comparatively investigated the CisPt-induced response of two different parental urothelial carcinoma cell lines (RT-112, J-82) with that of respective drug resistant variants (RT-112R, J-82R) obtained upon month-long CisPt selection. Parental RT-112 cells were ~2.5 fold more resistant to CisPt than J-82 cells and showed a different expression pattern of CisPt-related resistance factors. CisPt resistant RT-112R and J-82R variants revealed a 2–3-fold increased CisPt resistance as compared to their corresponding parental counterparts. Acquired CisPt resistance was accompanied by morphological alterations resembling epithelial mesenchymal transition (EMT). RT-112R cells revealed lower apoptotic frequency and more pronounced G2/M arrest following CisPt exposure than RT-112 cells, whereas no differences in death induction were observed between J-82 and J-82R cells. CisPt resistant J-82R cells however were characterized by a reduced formation of CisPt-induced DNA damage and related DNA damage response (DDR) as compared to J-82 cells. Such difference was not observed between RT-112R and RT-112 cells. J-82R cells showed an enhanced sensitivity to pharmacological inhibition of checkpoint kinase 1 (Chk1) and, moreover, could be re-sensitized to CisPt upon Chk1 inhibition. Based on the data we suggest that mechanisms of acquired CisPt resistance of individual UC cells are substantially different, with apoptosis- and DDR-related mechanisms being of particular relevance. Moreover, the findings indicate that targeting of Chk1 might be useful to overcome acquired CisPt resistance of certain subtypes of UC.

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Checkpoint Kinase Inhibitor AZD7762 Overcomes Cisplatin Resistance in Clear Cell Carcinoma of the Ovary

Abstract: The present study indicates that chemotherapy with AZD7762 and cisplatin should be explored as a treatment modality for women with ovarian clear cell carcinoma.

Cited by 37 publications

References 27 publications

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Checkpoint kinase inhibitor AZD7762 strongly sensitises urothelial carcinoma cells to gemcitabine

Recurrent ESR1–CCDC170 rearrangements in an aggressive subset of oestrogen receptor-positive breast cancers

Distinct mechanisms contribute to acquired cisplatin resistance of urothelial carcinoma cells

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