Ibrutinib potentiates antihepatocarcinogenic efficacy of sorafenib by targeting EGFR in tumor cells and BTK in immune cells in the stroma

Cho Hao Lin, Khadija H. Elkholy, Nissar A. Wani, Ding Li, Peng Hu, Juan M. Barajas, Lianbo Yu, Xiaoli Zhang, Samson T. Jacob, Wasif N. Khan, Xue Feng Bai, Anne M. Noonan, Kalpana Ghoshal

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, is a leading cause of cancer-related death worldwide because of rising incidence and limited therapy. Although treatment with sorafenib or lenvatinib is the standard of care in patients with advanced-stage HCC, the survival benefit from sorafenib is limited due to low response rate and drug resistance. Ibrutinib, an irreversible tyrosine kinase inhibitor (TKI) of the TEC (e.g., BTK) and ErbB (e.g., EGFR) families, is an approved treatment for B-cell malignancies. Here, we demonstrate that ibrutinib inhibits proliferation, spheroid formation, and clonogenic survival of HCC cells, including sorafenib-resistant cells. Mechanistically, ibrutinib inactivated EGFR and its downstream Akt and ERK signaling in HCC cells, and downregulated a set of critical genes involved in cell proliferation, migration, survival, and stemness, and upregulated genes promoting differentiation. Moreover, ibrutinib showed synergy with sorafenib or regorafenib, a sorafenib congener, by inducing apoptosis of HCC cells. In vivo, this TKI combination significantly inhibited HCC growth and prolonged survival of immune-deficient mice bearing human HCCLM3 xenograft tumors and immune-competent mice bearing orthotopic mouse Hepa tumors at a dose that did not exhibit systemic toxicity. In immune-competent mice, the ibrutinib–sorafenib combination reduced the numbers of BTKþ immune cells in the tumor microenvironment. Importantly, we found that the BTKþ immune cells were also enriched in the tumor microenvironment in a subset of primary human HCCs. Collectively, our findings implicate BTK signaling in hepatocarcinogenesis and support clinical trials of the sorafenib–ibrutinib combination for this deadly disease.

Original languageEnglish (US)
Pages (from-to)384-396
Number of pages13
JournalMolecular cancer therapeutics
Volume19
Issue number2
DOIs
StatePublished - Feb 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Lin, C. H., Elkholy, K. H., Wani, N. A., Li, D., Hu, P., Barajas, J. M., Yu, L., Zhang, X., Jacob, S. T., Khan, W. N., Bai, X. F., Noonan, A. M., & Ghoshal, K. (2020). Ibrutinib potentiates antihepatocarcinogenic efficacy of sorafenib by targeting EGFR in tumor cells and BTK in immune cells in the stroma. Molecular cancer therapeutics, 19(2), 384-396. https://doi.org/10.1158/1535-7163.MCT-19-0135