# The Emerging Role of Long Noncoding RNAs in Sorafenib Resistance Within Hepatocellular Carcinoma
### Primary Resistance
#### 1.2.1 Epidermal Growth Factor Receptor (EGFR) Activation  
Epidermal growth factor receptors (EGFRs) reside on the surface of epithelial cells and are the expression product of the proto-oncogene c-erbB1. After ligand binding, EGFRs can \begin{table}
\begin{tabular}{c c} \hline \hline  & **Sorafenib Resistance** \\ \hline
**Primary Resistance** & **Secondary Resistance** \\ \hline EGFR & Autophagy \\ \hline VEGFA & Exosomes \\ \hline Sestrin 2 & Ferroptosis \\ \hline JNK (MAPK Family) & Cancer stem cells \\ \hline  & Hypoxia \\ \hline  & ABC Transporters \\ \hline  & LncRNAs \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Major factors contributing to sorafenibity resistance at the primary (genetic factors) and secondary (during sorafenib treatment) levels are depicted. activate a series of downstream signaling pathways, which can help regulate cell growth and proliferation. EGFR overexpression and abnormal activation can be seen in most HCC patients [32; 33]. Erlotinib, an oral tyrosine kinase inhibitor of EGFR, has shown moderate antitumor activity against HCC [34]. In a study by [PERSON] et al. (2020), seven HCC-derived EGFR mutants studied were erlotinib-resistant and EGF-dependent. Erlotinib induced autophagy and apoptosis in cells harboring different EGFRs. The inhibition of EGFR phosphorylation by erlotinib was the decisive factor for the degree of apoptosis and autophagy amongst cells harboring EGFR mutants [35]. In another study by [PERSON] et al., the author used a human primary HCC and two human HCC cell lines, i.e., HepG3B and Huh7, to develop three sorafenib resistance HCC cell lines. The authors found that EGFR was significantly augmented in all three SR HCC cell lines. EGFR's tyrosine kinase activity inhibition observed with erlotinib and short hairpin RNA (shRNA) recovered the response of three SR HCC cell lines with the help of sorafenib, which suggests the crucial roles of EGFR tyrosine kinase and KLF4 in the induction of sorafenib resistance [36; 37; 38]. Several studies have highlighted the role of lncRNAs and associated targets/proteins that are frequently overexpressed in fibrosis, carcinoma, and cell injury due to renal pathologies and are often linked to tumor stage and metastasis [39; 40]. The expression patterns demonstrated that lncRNA targets and associated proteins might serve as biomarkers or therapeutic targets for HCC and RCC [39; 40]. In addition, the EGFR mutations and the single nucleotide polymorphism (SNP) of Aurora kinase A are associated with earlier tumor stages of several cancers [40; 41]. The EGFR, long noncoding RNA H19, LAMC1, and SNP rs3768617 could also increase the risk of cancer, causing the progression, metastasis, and expression with inflammation and oxidative stress markers of lung, liver, renal cancer, and chronic kidney diseases. Specific EGFR mutations, such as L858R and exon 19 in-frame deletions, are correlated with higher sensitivity in HCC, RCC, and lung cancer [39; 40]. EGFR inhibition, combined with sorafenib, can effectively suppress HCC progression [42]. Specifically, they found that dual targeting of EGFR and VEGFR, using the combination of erlotinib and sorafenib, significantly enhanced antitumor effects compared to either drug alone. The study underscores the role of EGFR in driving resistance through crosstalk with the VEGFR signaling pathway, suggesting that multi-targeted strategies could yield improved therapeutic outcomes in HCC [43]. Additionally, the potential of a novel EGFR inhibitor, afatinib, in sorafenib-resistant HCC models has been explored. The researchers demonstrated that afatinib suppressed EGFR phosphorylation and modulated the downstream PI3K/AKT and MAPK pathways, both of which contribute to resistance. Their findings suggest that afatinib could be an effective treatment option for overcoming sorafenib resistance by attenuating these critical survival pathways in HCC. LncRNA EGFR-AS1 was found to be upregulated in sorafenib-resistant HCC cells, promoting EGFR pathway activation.