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Insights into lenvatinib resistance: mechanisms, potential biomarkers, and strategies to enhance sensitivity

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Abstract

Lenvatinib is a multitargeted tyrosine kinase inhibitor capable of promoting apoptosis, suppressing angiogenesis, inhibiting tumor cell proliferation, and modulating the immune response. In multiple cancer types, lenvatinib has presented manageable safety and is currently approved as an effective first-line therapy. However, with the gradual increase in lenvatinib application, the inevitable progression of resistance to lenvatinib is becoming more prevalent. A series of recent researches have reported the mechanisms underlying the development of lenvatinib resistance in tumor therapy, which are related to the regulation of cell death or proliferation, histological transformation, metabolism, transport processes, and epigenetics. In this review, we aim to outline recent discoveries achieved in terms of the mechanisms and potential predictive biomarkers of lenvatinib resistance as well as to summarize untapped approaches available for improving the therapeutic efficacy of lenvatinib in patients with various types of cancers.

Graphical Abstract

This review focuses on current researches on the resistance mechanisms of lenvatinib, describes a series of potential biomarkers, outlines the current application status, and prospects of drugs used in combination with lenvatinib and summarizes ongoing clinical trials involving lenvatinib combination therapy.

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Abbreviations

RTKs:

Receptor tyrosine kinases

TKI:

Tyrosine kinase inhibitor

VEGFR:

Vascular endothelial growth factor receptor

HCC:

Hepatocellular carcinoma

FGFR:

Fibroblast growth factor receptor

PDGFR:

Platelet-derived growth factor receptor

RET:

Proto-oncogenes rearranged during transfection

KIT:

Stem cell factor receptor

PLCγ:

Phospholipase-Cγ

RAS:

Rat sarcoma

RAF:

Extracellular signal-regulated kinase

ERK:

Extracellular signal-regulated kinase

PI3K:

Phosphatidylinositol 3-kinase

AKT:

Ak strain transforming

OS:

Overall survival

DTC:

Differentiated thyroid cancer

RECIST 1.1:

Response Evaluation Criteria in Solid Tumors RECIST Version 1.1

RTKs:

Receptor tyrosine kinases

ETS-1:

E26 transformation-specific sequence 1

FGF:

Fibroblast growth factor

HBV:

Hepatitis C virus

MAPK:

Mitogen activated protein kinase

HGF:

Hepatocyte growth factor

c-MET:

C-mesenchymal-epithelial transition factor

NF1:

Neurofibromin 1

DUSP9:

Dual specificity phosphatase 9

CRISPR:

Clustered regularly interspaced short palindromic repeats

Cas9:

CRISPR-associated 9

FOXO3:

Forkhead box O3

gRNAs:

Guide RNAs

EGFR:

Epidermal growth factor receptor

IRF2:

Interferon regulatory factor 2

PHGDH:

Phosphoglycerate dehydrogenase

SSP:

Serine synthesis pathway

ROS:

Reactive oxygen species

α-KG:

α-Ketoglutarate

ITGB8:

Integrin subunit beta 8

EMT:

Epithelial–mesenchymal transition

ZEB1:

Zinc-finger E-box binding protein 1

CSCs:

Cancer stem cells

GSK3β:

Glycogen synthase kinase 3β

HNHA:

N-hydroxy-7-(2-naphthylthio) heptanomide

HSCs:

Hepatic stellate cells

ncRNAs:

Noncoding RNAs

sncRNAs:

Short ncRNAs

lncRNAs:

Long ncRNAs

miRNAs:

MicroRNAs

ceRNAs:

Competing endogenous RNAs

circRNAs:

Circular RNAs

circMED27:

CircRNA mediator complex subunit 27

USP28:

Ubiquitin-specific peptidase 28

pVEGFR 1–3:

Phosphorylated VEGFR 1–3

CGIs:

CpG islands

IGF1Rβ:

Insulin-like growth factor-1receptor β

HIF1α:

Hypoxia-inducible factor 1-α

HRE:

Hypoxia-responsive element

Pink-1:

PTEN-induced kinase-1

GSH:

Glutathione

P-gp:

P-glycoprotein

CRP:

C-reactive protein

AFP:

Alpha-fetoprotein

ORR:

Objective response rate

mPFS:

Median progression-free survival

Ang-2:

Angiopoietin-2

TME:

Tumor microenvironment

MDSCs:

Myeloid-derived suppressor cells

eMDSCs:

Early-stage MDSCs

PMN-MDSCs:

Polymorphonuclear MDSCs

M-MDSCs:

Mononuclear MDSCs

ATC:

Anaplastic thyroid cancer

PD-1:

Programmed death receptor-1

PAKs:

P21 activated kinases

XPO1:

Exportin 1

TEM:

Tie2-expressing macrophage

RCC:

Renal cell carcinoma

PTC:

Papillary thyroid cancer

Tregs:

Regulatory T-cells

IFN-γ:

Interferon-γ

MAIT:

Mucosal-associated invariant T cells

TNF:

Tumor necrosis factor

PFS:

Progression-free survival

FDA:

The US Food & Drug Administration

MSI-H/dMMR:

Microsatellite instability-high or mismatch repair-deficient

CNLC:

China liver cancer staging

TACE/HAIC:

Transarterial chemoembolization/Hepatic artery infusion chemotherapy

ICIs:

Immune check points inhibitors

USP22:

Ubiquitin-specific protease 22

PDX:

Patient-derived xenograft

PDO:

Patient-derived organoid

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Acknowledgements

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Funding

This work was supported by the National Bioengineering Research Center Cultivation Platform (WW201905), the National Natural Science Foundation of China (81900597, 81802897, 81901943, 81770648, 81970567), the Science and Technology Program of Guangdong Province (2019B020236003), the Science and Technology Program of Guangzhou City (201803040005), the Natural Science Foundation of Guangdong Province (2019A1515011698, 2021A1515012136, 2021A1515011156, 2021A1515010571), the Guangdong Basic and Applied Basic Research Foundation (2021A1515111058), the Guangzhou Basic and Applied Basic Research Foundation (202102020237), the Major talent project cultivation plan project (P02093).

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  1. Qiang You, Rong Li, Jia Yao, and Ying-Cai Zhang have contributed equally to this work.

Authors and Affiliations

  1. Department of Hepatic Surgery and Liver Transplantation Center of the Third Affiliated Hospital of Sun Yat-sen University; Organ Transplantation Research Center of Guangdong Province, Guangdong Province Engineering Laboratory for Transplantation Medicine, Guangzhou, 510630, Guangdong, China

    Qiang You, Jia Yao, Ying-Cai Zhang, Jie-Bin Zhang, Jia-Qi Xiao, Hai-Tian Chen, Hua Li, Jian Zhang, Jun Zheng & Yang Yang

  2. Guangdong Key Laboratory of Liver Disease Research, Key Laboratory of Liver Disease Biotherapy and Translational Medicine of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    Qiang You, Rong Li, Jia Yao, Ying-Cai Zhang, Jie-Bin Zhang, Jia-Qi Xiao, Hai-Tian Chen, Hua Li, Jian Zhang, Jun Zheng & Yang Yang

  3. Surgical ICU of the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    Xin Sui

  4. Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510630, China

    Cui-Cui Xiao

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Contributions

QY and RL carried out the literature searches, prepared figures and tables, did writing and editing; JY and YCZ did writing and editing; QY, JYC, XS, CCX, JBZ, JQX, and HTC did the literature searches and data interpretation; YY and JZ conceptualized the paper, did writing and editing. All authors read and approved the final manuscript.

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You, Q., Li, R., Yao, J. et al. Insights into lenvatinib resistance: mechanisms, potential biomarkers, and strategies to enhance sensitivity. Med Oncol 41, 75 (2024). https://doi.org/10.1007/s12032-023-02295-0

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