Table 1.

Mechanisms of resistance against sorafenib in HCC.

Factors	Mechanism Contributing to Resistance	Molecular Markers	Effect to Chemotherapy or Cellular Function
Drug Concentration
Drug efflux via ABC transporters	Overexpression of specific ABC transporters; genetic polymorphism	ABCB1; ABCC1; ABCC2; ABCC3; ABCG2	Decreased intracellular drug concentration
Drug uptake via SLC transport proteins	Downregulation of SLC transport proteins; genetic polymorphism; localization (plasma membrane expression only)	SLC22A1; SLC22A3; SLC46A3	Decreased intracellular drug concentration
Cellular Processes
Alteration of target molecule	Overexpression of drug target molecules; genetic polymorphism and mutation	Raf; VEGF	Promote angiogenesis; sustained activation of signaling pathway promoting cellular proliferation and growth
Alteration in signaling pathway	Overexpression and sustained activation of signaling pathway molecules; genetic polymorphism and mutation	EGFR Ras/Raf/MEK/ERK pathway)	Sustained activation of signaling pathway promoting cellular proliferation and growth
Intracellular drug metabolism	Genetic polymorphism in metabolizing enzymes	CYP3A5; CYP450; UGT1A9; UGT1A1	Decrease in drug metabolism
DNA repair	Overexpression sustained activation of DNA repair proteins; genetic polymorphism	APE1	Promote DNA repair therefore inhibiting apoptosis
Autophagy	Stress response that function as double-edged; Agonist or antagonist to treatment	ATGs	Promote cell survival and proliferation or otherwise
Intra- and Inter-Cellular Properties
Cancer Stem Cells	Presence of cancer stem cell properties poses survival advantage	CD133, CD90, EpCAM, ABCG2	Failed therapy
Tumor genetic heterogeneity	Tumoral heterogeneity dictates differential sensitivity of cells to chemotherapy within a tissue; cells ability for clonal expansion allows survival of resistant cells	-	Failed therapy