# Elucidating molecular mechanisms of cabozantinib resistance in liver cancer

> **NIH NIH R03** · LOYOLA UNIVERSITY CHICAGO · 2024 · $77,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10872437
- **Project number:** 1R03CA289838-01
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Wei Qiu
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $77,000
- **Award type:** 1
- **Project period:** 2024-03-05 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872437

## Citation

> US National Institutes of Health, RePORTER application 10872437, Elucidating molecular mechanisms of cabozantinib resistance in liver cancer (1R03CA289838-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10872437. Licensed CC0.

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