Liver cancer, as the sixth most common cancer and the third leading cause of cancer-related deaths1, is showing a rapidly increasing trend. Hepatocellular carcinoma (HCC) is one of the most common forms of primary liver cancer. In 2020, the global number of new cases of chronic liver diseases and cirrhosis caused by hepatocellular carcinoma reached as high as 905,700, of which 830,200 resulted in death2. The number of new cases of hepatocellular carcinoma in China reached 466,000, accounting for approximately 50% of the global new cases of hepatocellular carcinoma3,4. Among these, the number of deaths was 444,000, accounting for 45% of the global death tol5. In 2020, the five-year survival rate for new patients with hepatocellular carcinoma in China was only 12.1%, significantly lower than the overall five-year survival rate for cancer in China, which is 40.5%6, indicating the severe challenge of improving the therapy strategy of HCC. For individuals with HCC, systemic therapy becomes preferred treatment because more than 50% cases are discovered at an advanced stage7.
Sorafenib, also known as Nexavar, was initially used to treat advanced renal cell carcinoma that was inoperable. Subsequently, in 2007, it was approved by the FDA for the treatment of inoperable hepatocellular carcinoma, making it one of the approved therapies for hepatocellular carcinoma and one of the most common kinase inhibitors used in the treatment of solid tumors. Sorafenib is a multi-target tyrosine kinase inhibitor (TKI) that inhibit tumor angiogenesis and cell proliferation by targeting vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor (PDGDR) and Ras/Raf/MEK/ERK signaling pathways. In the randomized, double-blind, multi-center, phase III Sorafenib HCC Assessment Randomized Protocol (SHARP) trial, the median survival time for the placebo group was 7.9 months, while for the sorafenib group, it improved to 10.7 months8. However, roughly 30% of patients are able to derive benefits from sorafenib, and typically, this group develops resistance within a span of 6 months9. Therefore, it is urgent to explore the crucial mechanism of sorafenib resistance and explore combined treatment strategies that can improve the efficacy of sorafenib treatment in HCC.
Ferroptosis, a form of programmed cell death driven by iron-dependent lipid peroxidation (PCD), is distinctive in morphological, biochemical, and genetic levels compared to other forms of PCD. It was revealed and named by the Stockwell’s group after the discovery of erastin (a compound exhibiting selectivity for tumor cells bearing oncogenic RAS) and RAS-selective lethal 3 (RSL3, a drug candidate for cancer chemotherapy)10,11. Ferroptosis is characterized by depletion of glutathione (GSH), decrease in the activity of GPX4, and by an increase in ROS generation as consequences of the Fenton reaction12. The dysregulated ferroptosis has been participating in various physiological and pathological processes, which includes cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity13. In addition, sorafenib has demonstrated its ability to enhance ferroptosis primarily by inhibiting system xc- and increasing the intracellular iron levels14,15. Thus it is of significant to study the relationship between sorafenib-resistant and ferroptosis in order to optimize effectiveness of sorafenib.
In our study, we identified KDELR3 as the critical molecule in HCC sorafenib resistance. Mechanistically, KDELR3 expression increased after sorafenib treatment and inhibit lipid peroxidation and ferroptosis induced by sorafenib, thereby promoting HCC resistance. Our research may provide new targets and strategies for HCC systemic therapy.
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