Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Mar 14;15(6):1766.
doi: 10.3390/cancers15061766.

Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer

Mauro Viganò  1 , Marta La Milia  1 , Maria Vittoria Grassini  1   2 , Nicola Pugliese  3 , Massimo De Giorgio  1 , Stefano Fagiuoli  1   4
Affiliations
Review

Hepatotoxicity of Small Molecule Protein Kinase Inhibitors for Cancer

Mauro Viganò et al. Cancers (Basel). .

Abstract

Small molecule protein kinase inhibitors (PKIs) have become an effective strategy for cancer patients. However, hepatotoxicity is a major safety concern of these drugs, since the majority are reported to increase transaminases, and few of them (Idelalisib, Lapatinib, Pazopanib, Pexidartinib, Ponatinib, Regorafenib, Sunitinib) have a boxed label warning. The exact rate of PKI-induced hepatoxicity is not well defined due to the fact that the majority of data arise from pre-registration or registration trials on fairly selected patients, and the post-marketing data are often based only on the most severe described cases, whereas most real practice studies do not include drug-related hepatotoxicity as an end point. Although these side effects are usually reversible by dose adjustment or therapy suspension, or by switching to an alternative PKI, and fatality is uncommon, all patients undergoing PKIs should be carefully pre-evaluated and monitored. The management of this complication requires an individually tailored reappraisal of the risk/benefit ratio, especially in patients who are responding to therapy. This review reports the currently available data on the risk and management of hepatotoxicity of all the approved PKIs.

Keywords: cancer; drug-induced liver injury; hepatitis; hepatotoxicity; liver failure; tyrosine kinase inhibitors.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The different pathways of liver injury of the PKIs approved for cancer.
See this image and copyright information in PMC

References

    1. Krause D.S., Van Etten R.A. Tyrosine kinases as targets for cancer therapy. N. Engl. J. Med. 2005;353:172–187. doi: 10.1056/NEJMra044389. - DOI - PubMed
    1. Chen M.H., Kerkela R., Force T. Mechanisms of cardiomyopathy associated with tyrosine kinase inhibitor cancer therapeutics. Circulation. 2008;118:84–95. doi: 10.1161/CIRCULATIONAHA.108.776831. - DOI - PMC - PubMed
    1. Wilson L.J., Linley A., Hammond D.E., Hood F.E., Coulson J.M., MacEwan D.J., Ross S.J., Slupsky J.R., Smith P.D., Eyers P.A., et al. New perspectives, opportunities, and challenges in exploring the human protein kinome. Cancer Res. 2018;78:15–29. doi: 10.1158/0008-5472.CAN-17-2291. - DOI - PubMed
    1. Feng B., Xu J.J., Bi Y.A., Mireles R., Davidson R., Duignan D.B., Campbell S., Kostrubsky V.E., Dunn M.C., Smith A.R., et al. Role of hepatic transporters in the disposition and hepatotoxicity of a HER2 tyrosine kinase inhibitor CP-724,714. Toxicol. Sci. 2009;108:492–500. doi: 10.1093/toxsci/kfp033. - DOI - PubMed
    1. Shen T., Liu Y., Shang J., Xie Q., Li J., Yan M., Xu J., Niu J., Liu J., Watkins P.B., et al. Incidence and etiology of drug-induced liver injury in Mainland China. Gastroenterology. 2019;156:2230–2241. doi: 10.1053/j.gastro.2019.02.002. - DOI - PubMed

LinkOut - more resources