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Model Characteristics - Model:
Chronic cisplatin treatment promotes enhanced damage
repair and tumor progression in a LSL-KrasG12D/+ mouse model of lung cancer
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| Model Descriptor |
Chronic cisplatin treatment promotes enhanced damage
repair and tumor progression in a LSL-KrasG12D/+ mouse model of lung cancer
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| Official Nomenclature |
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| Genotype |
LSL-KrasG12D/+
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| Species |
Mouse (Mus musculus)
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| Strain |
129/Sv
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| Is This a Tool Strain? |
No
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Developmental Stage
(applies only to Zebrafish) |
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| Experimental Design |
Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Cisplatin is an example of a widely employed anti-cancer drug about which we have very little understanding of whether a given patient will be responsive or resistant to treatment. An improved understanding of the molecular and genetic basis of cisplatin response and resistance could significantly impact clinical strategies. Previously, mouse models of hematopoietic malignancies were successfully used to study the genetics of chemotherapy response. However, few attempts have been made to model chemotherapy resistance in mouse models of epithelial cancers. Here we used genetically engineered mouse models of lung cancer to dissect the molecular and genetic mechanisms of response and resistance to cisplatin therapy in vivo.
Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models (LSL-KrassupG12D/+/sup and a href=http://cancermodels.nci.nih.gov/camod/ViewModelAction.do?unprotected_method=populateModelCharacteristics&aModelID=150066386 target="_blank" LSL-KrassupG12D/+/sup;p53supfl/fl/sup/a) of human non-small-cell lung cancer (NSCLC).
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| Phenotype |
We show that lung tumors initially respond to cisplatin by sensing DNA damage, undergoing cell cycle arrest, and inducing apoptosis-leading to a significant reduction in tumor burden. Importantly, we demonstrate that this response does not depend on the tumor suppressor p53 or its tranional target, p21. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd). We demonstrate a novel role for PIDD as a regulator of chemotherapy response in human lung tumor cells.
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| Website for add. info |
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| Breeding Notes |
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| Sex Distribution of the Phenotype |
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| Submitted by |
caMOD, Curator
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| Principal Investigator / Lab |
Sweet-Cordero*, E. Alejandro
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| Comment |
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| Model Availability: This model is available from |
| Strain |
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