Elucidating molecular mechanisms of cabozantinib resistance in liver cancer

ABSTRACT Despite advancements in targeted molecular therapies, hepatocellular carcinoma (HCC) remains one of the deadliest malignancies worldwide, with an average 5-year survival rate of less than 18%. In 2007, the FDA approved sorafenib as a first-line treatment for HCC, but it has only a limited response rate and an increase in

overall survival of only 2.8 months. Since 2018, FDA has approved several targeted therapies for advanced HCC, including lenvatinib or atezolizumab in combination with bevacizumab as first-line treatments, and cabozantinib regorafenib, or nivolumab (or in combination with ipilimumab) as second-line treatments. Despite encouraging

results from these treatments, many patients still do not respond or acquire resistance to these drugs. This study will focus on the mechanisms of resistance to cabozantinib therapy in HCC, which currently remains unknown. Cabozantinib is a multi-kinase inhibitor. The FDA approved it as an effective second-line treatment for advanced

HCC patients who are previously treated with sorafenib or other systemic therapies in 2019. Despite its clinical efficacy (it improved overall survival by 2.2 months, and the median progression-free survival of 5.2 months, compared with 1.9 months for placebo), about 36% of patients did not respond to cabozantinib, and many

patients eventually developed resistance to cabozantinib after the initial response. Therefore, we plan to identify the molecular mechanisms of resistance to cabozantinib therapy in HCC, which will provide new insight into the mechanisms of drug resistance and tumor growth, and the development of new therapeutics to overcome

resistance to cabozantinib treatment. We have generated cabozantinib-resistant (CR) HCC cells and identified potential mechanisms for HCC cells to acquire CR: EGFR hyper-activation. We found that EGFR is hyper-activated in CR cells and tumors. We also demonstrated that both EGFR hyper-activation contributes to cabozantinib resistance in HCC. However, some

important questions remain to be answered. For example, what are the mechanisms by which EGFR is activated in CR cells (Aims 1 and 2)? The goal of this research is to answer this question, which would provide new insight into mechanisms of cabozantinib resistance and offer novel therapeutic strategies to treat HCC

patients.