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Review
. 2023 Apr 20:14:1153991.
doi: 10.3389/fphar.2023.1153991. eCollection 2023.

Lenvatinib resistance mechanism and potential ways to conquer

Wentao Bo  1 , Yan Chen  2
Affiliations
Review

Lenvatinib resistance mechanism and potential ways to conquer

Wentao Bo et al. Front Pharmacol. .

Abstract

Lenvatinib (LVN) has been appoved to treat advanced renal cell carcinoma, differentiated thyroid carcinoma, hepatocellular carcinoma. Further other cancer types also have been tried in pre-clinic and clinic without approvation by FDA. The extensive use of lenvastinib in clinical practice is sufficient to illustrate its important therapeutic role. Although the drug resistance has not arised largely in clinical, the studies focusing on the resistance of LVN increasingly. In order to keep up with the latest progress of resistance caused by LVN, we summerized the latest studies from identify published reports. In this review, we found the latest report about resistance caused by lenvatinib, which were contained the hotspot mechanism such as the epithelial-mesenchymal transition, ferroptosis, RNA modification and so on. The potential ways to conquer the resistance of LVN were embraced by nanotechnology, CRISPR technology and traditional combined strategy. The latest literature review of LVN caused resistance would bring some ways for further study of LVN. We call for more attention to the pharmacological parameters of LVN in clinic, which was rarely and would supply key elements for drug itself in human beings and help to find the resistance target or idea for further study.

Keywords: Lenvatinib; drug resistance; hepatocellular carcinoma; mechanism; pharmacological parameters.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

None
In this review, we summerized the absorption, distribution, metabolism, excretion of lenvatinib in clinic. The lastest mechanism and potential approches to overcome resistance caused by lenvatinib were supplied.
FIGURE 1
FIGURE 1
Overview of LVN pharmacodynamics and pharmacokinetics in vivo and the time line of Indication approval.
FIGURE 2
FIGURE 2
The resistance mechanism focuing on EMT, DNA damage, ferroptosis and autophagy of LVN. (A) EMT-mediated drug resistance via the FGFR onanaplastic thyroid cancer cells. (B) The combination of DNA damage response regulator with the inhibitor of CDC7 could bring out better therapuetic outcome of LVN in HCC via inhibiting DDR mediated drug resistance. (C) LVN involved in inhibition of ferroptosis participating process through blockage of the cystine import activity of GPX4. (D) Blocking intrinsic autophagic flux by knockout LAPTM5 or adding autophagy inhibtor, HCQ, could be overcome resistance caused by LVN.
FIGURE 3
FIGURE 3
The resistance mechanism focuing on RNA, RNA modification, cytokine and post-translational modification of LVN. (A)Sponging of microRNA-24-3p by MT1JP released BCL2L2, thereby forming a positive-feedback loop to realize LVN resistance. (B)YRDC knockdown showed decreased sensiticity to LVN via t6A modification. (C) Angiogenic cytokine overproduction confered in LVN-resistance in HCC and thereby contribute to tumor angiogenesis to increase the occurence of resistance. (D) Up-regulated ITGB8 in LVN resistance HCC cells leading to AKT’s ubiquitination to achieve resistance.
FIGURE 4
FIGURE 4
The potential ways to conquer LVN’s resistance containing the nanotechnology, combination therapy, blockage the resistance target and finding new target.
See this image and copyright information in PMC

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Grants and funding

This work was financially supported by the Science and Technology Program of Sichuan Province (No. 2022NSFSC0792); Beijing Xisike Clinical Oncology Research (No.Y-QL202101-0125); Technology Innovation Research and Development Project of Chengdu Science and Technology Bureau (No. 2022-YF05-01591-SN); Personalized Drug Therapy Key Laboratory of Sichuan Province Open Foundation (2021YB03); Chinese Pharmaceutical Association Hospital Phamacy department (CPA-Z05-ZC-2022-002).