Researchers at Ajou University Hospital have identified a novel approach to combat resistance to sorafenib and lenvatinib, two tyrosine kinase inhibitors (TKIs) commonly used to treat hepatocellular carcinoma (HCC).
The research team, led by Professors Cho Hyo-hung and Eun Jung-woo at the Gastroenterology Department of Ajou University Hospital, recently published a study to reveal a novel method to address resistance to sorafenib and lenvatinib and enhance the therapeutic efficacy of these anticancer drugs.
HCC treatment options encompass surgical interventions, embolization techniques, and medication regimens.
First-line systemic treatments such as tyrosine kinase inhibitors (TKIs) like sorafenib and lenvatinib, along with immunotherapies, are utilized to manage the progression of HCC in individuals with advanced, inoperable cases.
A major drawback of sorafenib and lenvatinib is that they are effective in only 10-20 percent of patients with advanced HCC, largely due to resistance.
The researchers aimed to investigate the mechanisms underlying the contribution of cancer-associated fibroblasts (CAFs) to resistance against TKIs, recognizing the crucial role of CAFs in promoting the growth of liver cancer cells and inducing resistance to anticancer drugs.
The results showed that cancer-associated fibroblasts (CAFs) secrete a substance known as plasma secreted phosphoprotein 1 (SPP1), which binds to integrins on the surface of hepatocellular carcinoma (HCC) cells, activating the RAF/ERK/STAT3 and PI3K/AKT/mTOR signaling pathways, and inducing chemoresistance.
Also, the study found that CAF-derived SPP1 promoted epithelial-mesenchymal transition, which plays an important role in the metastasis and invasion of HCC cells.
The researchers said SPP1 inhibitors in combination with TKI treatment suppressed the resistance to sorafenib and lenvatinib and epithelial-mesenchymal transition.
The hospital said this study is significant because it is the first to demonstrate that the degree of SPP1 expression can be used as a blood biomarker to predict treatment response and prognosis.
The study showed that patients with advanced HCC after sorafenib/lenvatinib with high SPP1 expression in the blood had poorer overall survival (OS) and progression-free survival (PFS) compared to those with low SPP1 expression.
"Sorafenib and lenvatinib are the main targeted therapies for patients with advanced HCCr because of their ability to inhibit multiple cancer activity pathways, but many patients fail to respond to the treatment due to resistance, which is why we conducted this study," Cho said.
"As a result, we identified that SPP1 is secreted by CAFs, which play an important role in chemotherapy resistance, metastasis, and invasion of HCC cells. We hope to contribute to the development of new therapies using SPP1 inhibitors," she added.
The study, titled, “Cancer-associated fibroblast-derived secreted phosphoprotein 1 contributes to resistance of hepatocellular carcinoma to sorafenib and lenvatinib,” has been published in the April issue of Cancer Communications (IF: 15.283), a world-leading medical journal in oncology and biology.