Cisplatin Effects in Lung Adenocarcinoma-bearing Mice,Alone and in Combination with Erlotinib

Cisplatin, a widely used and potent chemotherapeutic, causes nephrotoxicity leading to the development of acute kidney injury (AKI) in approximately 30% of patients who receive the drug (Sharp et al. 2016; Ozkok and Edelstein 2014). Longitudinal studies have also indicated that AKI is an independent risk factor for the development of chronic kidney disease (CKD; Chawla et al. 2014). However, the established murine model of cisplatin-induced kidney injury utilizes a single high dose of cisplatin that causes mice to become moribund three to four days after treatment. Thus, long-term sequelae pertaining to the development of CKD cannot be studied (Sharp and Siskind 2017). To address this issue, we optimized a repeated, low-dose regimen of cisplatin that better recapitulates how patients receive cisplatin. With this model, mice survive six or more months and develop renal fibrosis indicative of CKD (Sharp et al. 2016, 2018). To further improve on the model, we incorporated cancer, as only patients with cancer receive cisplatin. Using a transgenic model of lung adenocarcinoma, we found that mice with cancer had decreased survival, higher incidence of kidney injury (as measured by neutrophil gelatinase–associated lipocalin [NGAL]), and exacerbated renal fibrosis compared to noncancer mice when treated with cisplatin. Our goal was to better understand why mice with lung adenocarcinoma develop worsened renal fibrosis. Epidermal growth factor receptor (EGFR) signaling has been demonstrated to be a “double-edged sword” in kidney injury (Tang et al. 2013). During AKI, EGFR signaling is important for proliferation of proximal tubule cells. However, sustained activation of EGFR can result in fibrogenesis. Exploring EGFR signaling, we found that cancer mice treated with cisplatin had increased EGFR and phosphorylated EGFR Y1068 protein expression. This coincided with differential activation of EGFR downstream signaling pathways. Thus, we hypothesized that blocking EGFR activation with erlotinib (an FDA-approved EGFR inhibitor) would protect from the development of renal fibrosis, especially in mice with cancer. After treating both noncancer and cancer mice with a single low dose of cisplatin and erlotinib, we found that the combination of these two drugs caused severe kidney injury marked by a decrease in survival, loss of kidney function, and high levels of NGAL. Thus, we concluded that erlotinib is not a viable choice as a renoprotective agent for cisplatin-induced kidney injury using our clinically and physiologically relevant mouse model.