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EGFR activation limits the response of liver cancer to lenvatinib

Haojie Jin1,2, Yaoping Shi3, Yuanyuan Lv1

  • 1State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Nature
|July 22, 2021
PubMed

Insights

Combining lenvatinib with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, shows promise for treating advanced hepatocellular carcinoma (HCC). This combination therapy offers a new strategy for patients with advanced liver cancer who have high EGFR levels.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Hepatocellular carcinoma (HCC) is an aggressive liver cancer with limited treatment options.
  • Lenvatinib, a multi-target tyrosine kinase inhibitor, offers modest clinical benefit for advanced HCC.
  • Identifying novel therapeutic strategies is crucial for improving HCC patient outcomes.

Purpose of the Study:

  • To identify novel therapeutic targets and combinations for hepatocellular carcinoma (HCC).
  • To investigate the synthetic lethality of lenvatinib with other targeted therapies in liver cancer.
  • To evaluate the efficacy of combining lenvatinib with an epidermal growth factor receptor (EGFR) inhibitor.

Main Methods:

  • A kinome-centered CRISPR-Cas9 genetic screen was employed to identify synthetic lethal interactions with lenvatinib.
  • In vitro and in vivo experiments assessed the anti-proliferative effects of lenvatinib plus gefitinib in liver cancer models.
  • A clinical trial (NCT04642547) evaluated the combination therapy in patients with advanced HCC.

Main Results:

  • EGFR inhibition was found to be synthetic lethal with lenvatinib in liver cancer.
  • The combination of lenvatinib and gefitinib demonstrated potent anti-proliferative effects in vitro and in vivo.
  • Mechanistically, EGFR inhibition blocks the feedback activation of the EGFR-PAK2-ERK5 axis induced by lenvatinib.
  • Clinical treatment of advanced HCC patients unresponsive to lenvatinib with the combination yielded meaningful responses.

Conclusions:

  • The combination of lenvatinib and gefitinib represents a promising therapeutic strategy for advanced HCC.
  • This combination is particularly relevant for the approximately 50% of HCC patients with high EGFR levels.
  • Targeting the EGFR-PAK2-ERK5 axis offers a novel approach to overcome lenvatinib resistance in liver cancer.

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