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Ref Type | Journal Article | ||||||||||||
PMID | (18026198) | ||||||||||||
Authors | Tao Y, Zhang P, Frascogna V, Lecluse Y, Auperin A, Bourhis J, Deutsch E | ||||||||||||
Title | Enhancement of radiation response by inhibition of Aurora-A kinase using siRNA or a selective Aurora kinase inhibitor PHA680632 in p53-deficient cancer cells. | ||||||||||||
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Abstract Text | Overexpression of Aurora-A kinase has been correlated with cancer susceptibility and poor prognosis in several human cancers. In this study, we evaluated the effect of inhibition of Aurora-A kinase on cell cycle progression and tumour cell survival after exposure to ionising radiation (IR). Combined IR and Aurora-A inhibition by short interfering RNA (siRNA) or by PHA680632 (a selective Aurora kinase inhibitor with submicromolar activity against Aurora-A) prior to IR led to an enhancement of radiation-induced annexin V positive cells, micronuclei formation, and Brca1 foci formation only in cells with deficient p53. However, the drug brought about additive to sub-additive interaction with radiation with regard to in vitro clonogenic survival. Cell cycle analysis revealed a high >4N DNA content 24 h after PHA680632 exposure. DNA content >4N was reduced dramatically when cells were irradiated combined with PHA680632 simultaneously. In vivo xenografts (p53-/- HCT116) of a mice study showed enhanced tumour growth delay (TGD) after the PHA680632-IR combinatorial treatment compared with IR alone. These results demonstrate that PHA680632 in association with radiation leads to an additive effect in cancer cells, especially in the p53-deficient cells, but does not act as a radiosensitiser in vitro or in vivo. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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TP53 loss | colorectal cancer | sensitive | PHA-680632 + Radiotherapy | Preclinical - Pdx | Actionable | In a preclinical study, PHA-680632 synergized with radiotherapy to decrease tumor growth in Pdx models deficient in Tp53 (PMID: 18026198). | 18026198 |