Mechanisms of Reversible Sorafenib Resistance in Hepatocellular Carcinoma

Conventional wisdom in oncology is that drug resistance is a stable and heritable phenotype due largely to cancer cell acquisition of genetic alterations. Thus, most cancer agents are given as sequential lines of therapy since continued use of the same agent is considered futile after disease progression. The anti-angiogenic tyrosine kinase inhibitor sorafenib is the only approved treatment for advanced hepatocellular carcinoma (HCC) patients. Its efficacy is further hindered by intrinsic (upfront) and acquired drug resistance (initial response and subsequent relapse) and a lack of alternative therapies. Our laboratory previously demonstrated using a human xenograft model of locally advanced HCC that acquired resistance to sorafenib is reversible due to re-sensitization of the tumour following transfer of resistant cancer cells to new hosts. An implication is that continued or rechallenge treatment with sorafenib could be effective strategies in HCC. The mechanistic basis of reversible sorafenib resistance was investigated and was observed to be multifactorial. First, prompted by similar findings in HCC patients, tissue and plasma sorafenib levels of sorafenib were found to gradually decline over time in drug-resistant relative to sensitive tumour-bearing mice. These changes were partially attributed to tumoural induction of the sorafenib-metabolizing enzyme CYP3A4. Escalating the dose to restore drug levels resulted in excessive toxicity and did not completely reverse drug resistance. Second, sorafenib treatment was found to effectively inhibit angiogenesis to the same extent in responding as well as resistant tumours. Rather, tumours hijacked or â co-optedâ the host liver vasculature by becoming increasingly invasive and incorporating the adjacent parenchyma. Many of the changes associated with resistance were reversed by stopping treatment. Altogether, sorafenib treatment of HCC could be improved by 1) individualizing the dosage of drug; 2) prolonging anti-angiogenic treatment after disease progression; and 3) targeting co-opted vessels in conjunction with angiogenesis. From a survey of the literature, unstable forms of drug resistance may be applicable to other classes of anti-cancer therapy, including agents that directly target cancer cells. This phenomenon appears to be highly under-appreciated as a characteristic of cancers but offers important opportunities to extend the utility of many existing cancer drugs.

Department dc:contributor.department

Medical Biophysics

Year dc:date.issued

2016

Author dc:creator

• Kuczynski, Elizabeth Anne

Advisor dc:contributor.advisor

• Kerbel, Robert S

• angiogenesis
• hepatocellular carcinoma
• liver cancer
• resistance
• vessel co-option
• xenograft

Handle dc:identifier.uri

http://hdl.handle.net/1807/75322

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/75322