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Case Reports
. 2018 Sep 25;19(10):2902.
doi: 10.3390/ijms19102902.

Renal Injury during Long-Term Crizotinib Therapy

Taro Yasuma  1   2 , Tetsu Kobayashi  3 , Corina N D'Alessandro-Gabazza  4 , Hajime Fujimoto  5 , Kentaro Ito  6 , Yoichi Nishii  7 , Kota Nishihama  8 , Prince Baffour Tonto  9 , Atsuro Takeshita  10   11 , Masaaki Toda  12 , Esteban C Gabazza  13 , Osamu Taguchi  14 , Shigenori Yonemura  15 , Osamu Hataji  16
Affiliations
Case Reports

Renal Injury during Long-Term Crizotinib Therapy

Taro Yasuma et al. Int J Mol Sci. .

Abstract

Crizotinib is highly effective against anaplastic lymphoma kinase-positive and c-ros oncogen1-positive non-small cell lung cancer. Renal dysfunction is associated with crizotinib therapy but the mechanism is unknown. Here, we report a case of anaplastic lymphoma kinase positive non-small cell lung cancer showing multiple cysts and dysfunction of the kidneys during crizotinib administration. We also present results demonstrating that long-term crizotinib treatment induces fibrosis and dysfunction of the kidneys by activating the tumor necrosis factor-α/nuclear factor-κB signaling pathway. In conclusion, this study shows the renal detrimental effects of crizotinib, suggesting the need of careful monitoring of renal function during crizotinib therapy.

Keywords: anaplastic lymphoma kinase; crizotinib; cystic formation; fibrosis; lung cancer; renal injury.

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Conflict of interest statement

The authors report no declarations of interest regarding data reported in this manuscript.

Figures

Figure 1
Figure 1
Chest and abdominal computed tomography (CT) in the present case. Chest CT of the patient with ALK-positive NSCLC at diagnosis (A), after 1 month (B), and after 11 months (C) of crizotinib therapy. Abdominal CT of the patient before therapy with crizotinib (D), 11 months after crizotinib therapy (E), 13 months (F) after crizotinib therapy, and after stopping the drug (G). NSCLC: non–small cell lung cancer; ALK: anaplastic lymphoma kinase.
Figure 2
Figure 2
Enlargement of pre-existing cyst after crizotinib administration. Micro-CT images of a mouse show enlargement of kidney cyst after crizotinib treatment (A) red arrowheads. Periodic acid–Schiff staining showed compressed glomeruli and tubules (B) upper panel at ×40 and lower panel at ×100 magnification. The micro-CT of other mice with no pre-existing cyst show no cystic formation after crizotinib (C).
Figure 3
Figure 3
Renal fibrosis and increased markers of renal failure after crizotinib administration. Periodic acid-Schiff staining shows glomerular mesangial expansion in mice treated with crizotinib compared to untreated mice (A), scale bar indicates 10 µm. Masson’s trichrome staining shows increased glomerular and interstitial fibrosis in the kidneys from mice treated with crizotinib compared to those from untreated mice (B), scale bar indicates 20 µm. The blood level of creatinine, urine levels of urea nitrogen and creatinine and the ratio of total protein to creatinine in urine were significantly different between control and crizotinib groups (C). Data are mean ± SD. Control group n = 3; crizotinib group n = 5. * p < 0.05 versus control group.
Figure 4
Figure 4
Cytokines, proteases and signal pathways after crizotinib administration. Increased mRNA expression of Col1a1, TGFβ1, IL-6, TNFα, and MMP2 in mice treated with crizotinib compared to untreated mice (A). Significant difference in phosphorylation level of c-Met and IκB between mice treated with and without crizotinib (B). Data are mean ± SD. Control group n = 3; crizotinib group n = 5. * p < 0.05 versus control group.
See this image and copyright information in PMC

References

    1. Christensen J.G., Zou H.Y., Arango M.E., Li Q., Lee J.H., McDonnell S.R., Yamazaki S., Alton G.R., Mroczkowski B., Los G. Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma. Mol. Cancer Ther. 2007;6:3314–3322. doi: 10.1158/1535-7163.MCT-07-0365. - DOI - PubMed
    1. Zou H.Y., Li Q., Lee J.H., Arango M.E., McDonnell S.R., Yamazaki S., Koudriakova T.B., Alton G., Cui J.J., Kung P.P., et al. An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007;67:4408–4417. doi: 10.1158/0008-5472.CAN-06-4443. - DOI - PubMed
    1. Blackhall F.H., Peters S., Bubendorf L., Dafni U., Kerr K.M., Hager H., Soltermann A., O'Byrne K.J., Dooms C., Sejda A., et al. Prevalence and clinical outcomes for patients with ALK-positive resected stage I to III adenocarcinoma: Results from the European Thoracic Oncology Platform Lungscape Project. J. Clin. Oncol. 2014;32:2780–2787. doi: 10.1200/JCO.2013.54.5921. - DOI - PubMed
    1. Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., et al. Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell. 2007;131:1190–1203. doi: 10.1016/j.cell.2007.11.025. - DOI - PubMed
    1. Soda M., Choi Y.L., Enomoto M., Takada S., Yamashita Y., Ishikawa S., Fujiwara S., Watanabe H., Kurashina K., Hatanaka H., et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561–566. doi: 10.1038/nature05945. - DOI - PubMed

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