Kyungpook National University Hospital Uncovers Strategy to Overcome Drug Resistance by Blocking Amino Acids in Liver Cancer Cells

Research Team of Professors Park Geun-gyu and Choi Yeon-kyung, Department of Endocrinology and Metabolism

Schematic diagram of the combined effect of sorafenib and giant cell action inhibitors.

[Asia Economy Yeongnam Reporting Headquarters Reporter Dongguk Lee] A research team led by Professors Geun-Kyu Park and Yeon-Kyung Choi from the Department of Endocrinology and Metabolism at Kyungpook National University Hospital (co-first authors Research Professor Jun-Gyu Byun and PhD candidate Seung-Hyung Lee) has identified that liver cancer cells exposed to sorafenib (a multi-target kinase inhibitor and anticancer drug) induce drug resistance by supplying amino acids through macropinocytosis.

Macropinocytosis is a process where extracellular fluid and nutrients enter the cell through large heterogeneous vesicles.

In the nutrient-deficient tumor microenvironment, macropinocytosis supports cancer cell growth and helps overcome energy stress. It is known that mutations in oncogenes such as KRAS and PTEN increase macropinocytosis.

Despite recent advances in immune-based therapies for liver cancer, sorafenib remains the most effective single-agent therapy; however, it has limitations due to high recurrence rates and resistance, necessitating treatment strategies to improve drug response.

(From left) Professor Geun-gyu Park, Professor Yeon-kyung Choi, Research Professor Jun-gyu Byun, and PhD candidate Seung-hyung Lee from the Department of Endocrinology and Metabolism Research Team at Kyungpook National University Hospital.

The endocrinology and metabolism research team at this hospital focused on the fact that macropinocytosis induced in liver cancer cells offsets the anticancer effects of sorafenib, aiming to elucidate the impact and mechanism of macropinocytosis on sorafenib resistance.

The study revealed that although sorafenib induces ferroptosis (a form of cell death) in liver cancer cells, cell death is suppressed due to amino acids supplied via macropinocytosis, leading to drug resistance.

They also confirmed that co-treatment with amiloride, a hypertension medication, inhibits macropinocytosis and can overcome anticancer drug resistance.

Professor Geun-Kyu Park stated, “While macropinocytosis in cancer cells is known to be induced by mutations in oncogenes, this study is the first to demonstrate that macropinocytosis is induced by anticancer drugs in liver cancer cells, causing drug resistance independent of oncogene mutations. Based on these findings, combination therapy of sorafenib and macropinocytosis inhibitors is expected to become a new therapeutic strategy.”

This research was supported by the Mid-Career Researcher Support Program, Bio and Medical Technology Development Program, and Leading Research Center Support Program funded by the Ministry of Science and ICT and the National Research Foundation of Korea. The results were published in the world-renowned oncology journal, Journal of Experimental & Clinical Cancer Research (IF: 11.161).

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