A research team at Kyungpook National University Hospital (KNUH) has discovered that liver cancer cells exposed to sorafenib induce anticancer drug resistance by supplying amino acids through macropinocytosis.

The researchers expect that the finding would lead to a new method to increase the effectiveness of liver cancer treatment.

Despite recent advances in immunotherapy for liver cancer, sorafenib is the most effective monotherapy. However, it has limitations due to its high recurrence rate and resistance, which, in turn, has raised the need for a new strategy to improve drug response.

Therefore, the team, led by Professors Park Geun-gyu and Choi Yeon-kyung of the Department of Endocrinology and Metabolism, tried to elucidate the effect and mechanism of macropinocytosis on the induction of resistance to sorafenib, noting that macropigmentation induced in liver cancer cells cancel the anticancer effect of sorafenib.

The result showed that sorafenib induced ferroptosis of liver cancer cells but inhibited apoptosis due to amino acids supplied by macropinocytosis, which induced resistance to anticancer drugs.

Researchers also confirmed that they could overcome resistance to anticancer drugs by inhibiting the action of macrophages by using the antihypertensive drug Amiloride with sorafenib.

“It has been known that mutations in oncogenes cause macropinocytosis in cancer, but our study has found that anticancer agents in liver cancer cells cause macropinocytosis action to induce drug resistance, not oncogene mutations,” Professor Park said. “Based on this study's results, we expect a combination therapy of sorafenib and a macropinocytosis inhibitor to become a new treatment strategy.”

The study results were published in the Journal of Experimental and Clinical Cancer Research.