Table 1.

Summary of Approaches

Target of Analysis	How it affects Resistance	Mechanisms involved	Possible Combination Therapies paired with Lenvatinib
c-MET and HGF	Increasing HGF in cells high in c-MET expression caused resistance to Lenvatinib. Lenvatinib exposure also increases phosphorylation of c-MET.	HGF binds to c-MET causing autophosphorylation which activates PI3K/AKT and MAPK/ERK pathways. HGF also induces EMT-induced resistance.	c-MET inhibitors such as PHA-665752, miR-128–3p, and Capmatinib.
DUSP9	DUSP9 loss induces Lenvatinib resistance.	DUSP9 loss activates the MAPK/ERK signaling pathway, which inactivates and degrades FOXO3, a tumor suppressor, inducing Lenvatinib resistance.	Trametinib
EGFR	Inhibiting EGFR with Erlotinib reversed resistance in Lenvatinib resistant cells.	Reactive Oxygen Species caused enhanced EGFR activation leading to Lenvatinib resistance due to EGFR activating the Ras/MAPK pathway.	Erlotinib
Fibronectin	Inhibiting Fibronectin expression re-sensitizes resistant cells to Lenvatinib.	Transcription factors such as HIF-1α are induced under hypoxia. Microenvironments of HCC tumors are often hypoxic. The induction of transcription factors enhances the production of fibronectin resulting in Lenvatinib resistance. Additionally, hypoxia induces the MAPK pathway, upregulating Fibronectin and resulting in Lenvatinib resistance.	MAPK inhibitors
FZD10	Increased expression of FZD10 is associated with a poor response to Lenvatinib and faster resistance.	METTL3 and YTHDF2 modify and stabilize FZD10 mRNA respectively. This eventually promotes β-catenin and YAP1 to transcribe genes involved in tumorigenesis as well as c-Jun. C-Jun activates the MEK/ERK pathway and promotes transcription of METTL3.	FZD10 or β-catenin inhibition using an adeno-associated virus.
ITGB8	Increased ITGB8 expression promotes HCC growth and Lenvatinib resistance.	Increased expression of ITGB8 in turn increases the expression of HSP90. HSP90 inhibits AKT ubiquitination and promotes AKT stabilization. When that occurs, the AKT signaling pathway has increased activity inducing Lenvatinib resistance.	MK-2206 or 17-AAG
IRF2	Decreased levels of IRF2 augment Lenvatinib sensitivity.	Resistance to Lenvatinib induced by IRF2 overexpression can be partially reversed by inhibiting the expression of β-catenin/activation of Wnt signaling. The exact mechanism is unclear.	XAV-939
NF1	NF1 loss induces Lenvatinib resistance.	NF1 loss reactivates the PI3K/AKT and MAPK/ERK signaling pathways. Activation of these pathways inactivates and degrades FOXO3, a tumor suppressor, inducing Lenvatinib resistance.	Trametinib
Sophoridine	Sophoridine suppressed tumor growth of HCC in a dose-dependent manner, inhibited growth of individual clones of resistant cells, and induced apoptosis of resistant cells in a dose-dependent manner.	Sophoridine decreases ETS-1 expression. ETS-1 promotes VEGFR2 expression, and when knocked down, sensitized resistant cells to Lenvatinib. Sophoridine had a similar affect to cells where ETS-1 was knocked down. Sophoridine also inhibits the RAS/MEK/ERK axis.	Sophoridine
YRDC	YRDC-KD cells were more resistant to Lenvatinib.	YRDC modulates the translation of key genes (KRAS) in pathways of anti-cancer activity (Lenvatinib).	KRAS inhibitor