Repeated administration of cisplatin increases EGFR/EGFR activation and renal fibrosis in Kras4bG12D lung adenocarcinoma-bearing mice, but kidney injury is further exacerbated with erlotinib/cisplatin combination treatment
Grade Level at Time of Presentation
Senior
Major
Chemistry, track in Biochemistry
Institution
University of Louisville
KY House District #
54
KY Senate District #
15
Faculty Advisor/ Mentor
Leah Siskind, PhD
Department
Dept. of Pharmacology and Toxicology
Abstract
Cisplatin (CDDP) is a first-choice therapy for many cancers, but 30% of patients develop acute kidney injury (AKI), which can progress to chronic kidney disease (CKD). Currently, there are no therapeutic interventions for CDDP-induced AKI or CKD. Clinically, only cancer patients receive CDDP, and it is administered in repeated, low doses to curtail CDDP nephrotoxicity.
Previously, we optimized a repeated dosing regimen of CDDP (7mg/kg 1x/wk for 4wks), which causes CKD in mice, but the effect of cancer in this model has yet to be examined.
Our goal was to determine how incorporating cancer into our mouse model of CDDP nephrotoxicity may alter kidney injury. We utilized a Kras4bG12D transgenic mouse that develops lung adenocarcinoma and treated non-cancer and cancer mice with repeated CDDP dosing. Indices of kidney injury, function, and renal fibrosis were obtained using ELISAs, QRTPCR, and IHC staining for repeated CDDP and subsequent erlotinib studies.
CDDP-treated cancer mice had lower survival and worsened fibrosis as indicated by Sirius red staining and myofibroblast levels compared to CDDP-treated non-cancer mice. Western blot analysis indicated CDDP-treated cancer mice had increased EGFR/pEGFR Y1068 levels. Thus, we hypothesized treating cancer mice with erlotinib (EGFR inhibitor) in combination with CDDP would decrease EGFR activation and subsequently renal fibrosis. Administration of erlotinib as a renoprotective (25mg/kg 1x/day for 7 days) with one dose of 7mg/kg CDDP caused severe AKI compared to CDDP-only group. Additionally, we used erlotinib as an injury-ameliorating agent by administering erlotinib (25mg/kg 1x/day for 30 days) after repeated dosing of CDDP in cancer mice.
Using a lung-adenocarcinoma model with our mouse model of CDDP kidney injury, we have shown cancerous mice have worsened AKI/CKD when treated with CDDP. Additionally, targeting EGFR with erlotinib further exacerbated renal injury. Results obtained using erlotinib post-CDDP treatment to ameliorate renal fibrosis will require follow-up studies.
Repeated administration of cisplatin increases EGFR/EGFR activation and renal fibrosis in Kras4bG12D lung adenocarcinoma-bearing mice, but kidney injury is further exacerbated with erlotinib/cisplatin combination treatment
Cisplatin (CDDP) is a first-choice therapy for many cancers, but 30% of patients develop acute kidney injury (AKI), which can progress to chronic kidney disease (CKD). Currently, there are no therapeutic interventions for CDDP-induced AKI or CKD. Clinically, only cancer patients receive CDDP, and it is administered in repeated, low doses to curtail CDDP nephrotoxicity.
Previously, we optimized a repeated dosing regimen of CDDP (7mg/kg 1x/wk for 4wks), which causes CKD in mice, but the effect of cancer in this model has yet to be examined.
Our goal was to determine how incorporating cancer into our mouse model of CDDP nephrotoxicity may alter kidney injury. We utilized a Kras4bG12D transgenic mouse that develops lung adenocarcinoma and treated non-cancer and cancer mice with repeated CDDP dosing. Indices of kidney injury, function, and renal fibrosis were obtained using ELISAs, QRTPCR, and IHC staining for repeated CDDP and subsequent erlotinib studies.
CDDP-treated cancer mice had lower survival and worsened fibrosis as indicated by Sirius red staining and myofibroblast levels compared to CDDP-treated non-cancer mice. Western blot analysis indicated CDDP-treated cancer mice had increased EGFR/pEGFR Y1068 levels. Thus, we hypothesized treating cancer mice with erlotinib (EGFR inhibitor) in combination with CDDP would decrease EGFR activation and subsequently renal fibrosis. Administration of erlotinib as a renoprotective (25mg/kg 1x/day for 7 days) with one dose of 7mg/kg CDDP caused severe AKI compared to CDDP-only group. Additionally, we used erlotinib as an injury-ameliorating agent by administering erlotinib (25mg/kg 1x/day for 30 days) after repeated dosing of CDDP in cancer mice.
Using a lung-adenocarcinoma model with our mouse model of CDDP kidney injury, we have shown cancerous mice have worsened AKI/CKD when treated with CDDP. Additionally, targeting EGFR with erlotinib further exacerbated renal injury. Results obtained using erlotinib post-CDDP treatment to ameliorate renal fibrosis will require follow-up studies.