The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC), a liver cancer originating from hepatocytes, is a major health concern and among the most common malignancies worldwide. Sorafenib, approved by the U.S. F.D.A., is the primary first-line treatment for patients with advanced HCC. While the preferred first-line systemic regimen for HCC is immunotherapy with Atezolizumab plus bevacizumab or Tremelimumab-actl + durvalumab, Sorafenib is still an alternative recommended regimen. While some patients with advanced HCC may benefit from Sorafenib treatment, most eventually develop resistance, leading to poor prognosis. Long noncoding RNAs (lncRNAs) have been found to play a critical role in tumorigenesis and the development of HCC, as well as other cancers. They are also key players in tumor drug resistance, though the mechanisms of lncRNAs in Sorafenib resistance in HCC remain poorly understood. This review summarizes the molecular mechanisms contributing to Sorafenib resistance in HCC with their potential correlation with lncRNAs, including the roles of transporters, receptors, cell death regulation, and other influencing factors.

Keywords: EGFR; Sorafenib resistance; VEGFA; autophagy; hepatocellular carcinoma (HCC); long noncoding RNA (LncRNA); proteomics; renal cell carcinoma (RCC).

Figure 1

Sorafenib, an anticancer drug, is transported into the cell through SLC proteins (OCT1 and FKSG16) and undergoes metabolism via CYP3A4 (phase 1) and phase 2 U.D.P. glucuronosyltransferase 1A9 (UGT1A9) to form the M1-M8 metabolites. Among the metabolites of sorafenib, M2, M4 (demethylation), and M5 (oxidative metabolite) were found to inhibit vascular endothelial growth factor receptors (VEGFRs). Sorafenib resistance: On the left side of the figure, sorafenib, an anticancer drug, is taken up into the cell primarily through the solute carrier (SLC proteins) and the organic cation transporter (OCT1). Once inside, sorafenib undergoes metabolism via CYP3A4 (phase 1) and phase 2 U.D.P. glucuronosyltransferase 1A9 (UGT1A9) to form the M1-M6 metabolites, including sorafenib glucuronide. These metabolites, particularly M2, can undergo glucuronidation to further reduce their activity. Sorafenib and its metabolites are also effluxed out of the cell by ABC transporters, including BCRP and MRP2, which contribute to drug re-sistance.

Figure 2

Sorafenib induces the AMPK (AMP-activated protein kinase) pathway by increasing the ATP, initiating autophagy via AMPK, and through mTORC1 inhibition or ULK1 activation. Sorafenib can inhibit mTORC1 via the ERK pathway by inhibiting PTEN (Phosphatase and Tensin Homolog), but it can also activate mTORC1 through Akt activation (key regulators of P13K/AKT/mTOR pathway); it also inhibits ERK, further reducing mTOR activity. In addition, miRNAs are involved in sorafenib-mediated autophagy regulation. Sorafenib increases miR-21 and 25 expression, suppressing autophagy and decreasing FBXW7 protein expression, downregulating PTEN expression, and subsequently activating Akt.