VEGFR inhibition leading to Keratinocyte differentiation-associate Hand-foot skin reaction

VEGFR inhibition induced Hand-foot skin reaction

Brendan Ferreri-Hanberry

BY-SA

2.6

Drug-induced skin toxicity or cutaneous adverse drug reactions (CADRs) refer to the various clinical manifestations affecting the skin, mucosae, and adnexa that are induced by medications. These reactions encompass a range of symptoms resulting from drug exposure. The molecular mechanisms underlying these CADRs include hyper-proliferation, hyper-differentiation, epithelial-mesenchymal transition (EMT), and cell death of Keratinocytes. However, a universal mechanism for CADRs is not currently available. Among the drugs causing cutaneous toxicity, small molecule kinase inhibitors (SMKIs) stand out as a distinct class. Unlike traditional cytotoxic chemotherapy, SMKIs exhibit specific anti-cancer effects while reducing the incidence of side effects. Nonetheless, SMKIs are associated with unique toxicities, especially cutaneous toxicity. Notably, skin adverse reactions are most frequently observed in patients treated with VEGFR inhibitors such as Sorafenib and Sunitinib, impacting both treatment efficacy and patient quality of life. Drawing from previous research, a specific adverse outcome pathway (AOP) has been identified, potentially mediated by vascular endothelial growth factor receptor (VEGFR), likely offering insights into specific molecular mechanisms contributing to skin toxicity. In this AOP, the Molecular Initiating Event (MIE) is "VEGFR Inhibition," triggering six Key Events (KEs): " The release of s-HBEGF from HUVECs," "s-HBEGF-binding with EGFR," " Phosphorylation of JNK2," "Activates SIRT1 ser27 phosphorylation," "Keratinocyte hyper-differentiation," and "Hyper-keratosis."Ultimately, this pathway culminates in the Adverse Outcome (AO) of Hand-Foot Skin Reaction. Vascular endothelial growth factor receptor (VEGFR), a member of the protein tyrosine kinases (PTK) receptor family, is a key signal receptor for angiogenesis and has become one of the most effective targets for anti-tumor therapy [1]. When compared to antibodies targeting VEGF or VEGFR, the VEGFR tyrosine kinase inhibitors (VEGFR TKIs) have the advantage of oral availability, which is considered as a major convenience benefit for patients nowadays [2]. Currently, the US Food and Drug Administration (FDA) has approved several VEGFR TKIs, including sorafenib, sunitinib, pazopanib, vandetanib, axitinib, regorafenib, cabozantinib, nintedanib and lenvatinib. However, the inhibition of VEGFR is usually associated with some toxicities. There are some examples, including mechanism and clinical outcomes, related to the toxicities of VEGFR inhibitors. <ul> <li>Cardiovascular toxicity: The use of VEGFR TKIs significantly increases the risk of developing cardiovascular toxicities, such as hypertension, bleeding, and cardiac dysfunction. It has also been reported that selective targeting of CCN2 for autophagic degradation in cardiomyocytes results in sunitinib-stimulated cardiomyocyte apoptosis and cardiotoxicity [3,4,5].</li> <li value="50">Hepatotoxicity: Although, a meta-analysis of randomized controlled trials which was conducted to determine the relative risk of hepatotoxicity with VEGFR TKIs showed that the incidence of hepatic failure with VEGFR TKIs was 0.8%. The potential for serious hepatotoxicity with several VEGFR TKIs is believed to be high enough to require a boxed label warning by FDA [6]. Mechanistically, regorafenib-induced liver injury is due to the inhibition of EphA2 Ser897 phosphorylation and the ubiquitination of p53 by altering the intracellular localization of mouse double minute 2 (MDM2) by affecting the extracellular signal-regulated kinase (ERK)/MDM2 axis [7].</li> <li value="50"><a name="_Hlk166954515">Cutaneous toxicity</a>: The number of VEGFR TKIs used as an anti-cancer agent is rapidly increasing, but cutaneous adverse events are among the most frequently observed in patients receiving VEGFR TKIs. Common cutaneous adverse reactions caused by VEGFR TKIs are HFSR, Rash, Skin discoloration and Dry skin [8]. In VEGFR TKIs-induced cutaneous toxicity, vandetanib is able to upregulate levels of apoptosis-related proteins in keratinocytes, downregulates mitochondrial membrane potential, increases mitochondrial ROS production and promotes DNA damage in keratinocytes. Vandetanib can also activate adaptive autophagy [9].</li> </ul> One of the most common cutaneous toxicities associated with VEGFR TKIs is HFSR. Here are some details. <ul> <li>Clinical Presentation and treatment: HFSR is typically characterized by dysesthesia, paresthesia, erythema, and hyperkeratosis affecting the palms and soles. These symptoms have a serious impact on the lives of patients, severely limiting their ability to perform activities of daily living and causing an enormous financial burden, which in turn leads to a reduced quality of life. However, there is a little high-quality evidence to support specific reactive treatments for HFSR induced by VRGFR TKIs..Best therapeutic management remains uncertain [10,11,12].</li> <li value="50">Prevalence: A meta-analysis and review investigative the phase II or III trials of anti-VEGFR TKIs between 2000 and 2013 involving ≥ 50 patients in PubMed. It demonstrated that all grades rash, HFSR and pruritus were associated with VEGFR TKIs. Vandetanib had the highest incidence of rash (41%), while sorafenib was most frequently associated with HFSR (37%) and pruritus (14%) [13]. Another systematic review and meta-analysis also suggested that the use of VEGFR TKIs increased the risk of all-grade HFSR and high-grade (≥grade 3) HFSR.</li> <li value="50">Mechanism: Luo found that s-HBEGF released from vascular endothelial cells activates the epidermal growth factor receptor (EGFR) on keratinocytes and promotes the phosphorylation of c-Jun N-terminal kinase 2 (JNK2), which stabilizes sirtuin 1 (SIRT1), an essential keratinization inducer, and ultimately leading to HFSR. However, it is not clear whether this mechanism of sorafenib is applicable to other VEGFR TKIs [15].</li> </ul> Therefore, influenced by the pathway that sorafenib acts on the keratinocyte mechanism by affecting the release of HBEGF from vascular endothelial cells, this AOP aims to explore the pathway that is broadly applicable to the VEGFR TKIs induced HFSR. This identification of AOP may improve the understanding of cutaneous adverse drug reactions, which can not only explain the high incidence of HFSR associated with anticancer drugs, but also open a new insight into the vascular endothelial cell-keratinocyte axis. It is also a source of new treatment for a range of cutaneous toxicity adverse outcomes such as HFSR.

<div> <table class="table table-bordered table-fullwidth"> <thead> <tr> <th>Modulating Factor (MF)</th> <th>Influence or Outcome</th> <th>KER(s) involved</th> </tr> </thead> <tbody> <tr> <td> </td> <td> </td> <td> </td> </tr> </tbody> </table> </div>

[1] Cheng K, Liu CF, Rao GW. Anti-angiogenic Agents: A Review on Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors. Curr Med Chem. 2021;28(13):2540-2564. [2] Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a review. Eur J Cancer. 2006 Dec;42(18):3127-39. [3] Li J, Gu J. Cardiovascular Toxicities with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Cancer Patients: A Meta-Analysis of 77 Randomized Controlled Trials. Clin Drug Investig. 2018 Dec;38(12):1109-1123. [4] Jiang L, Ping L, Yan H, et, al. Cardiovascular toxicity induced by anti-VEGF/VEGFR agents: a special focus on definitions, diagnoses, mechanisms and management. Expert Opin Drug Metab Toxicol. 2020 Sep;16(9):823-835. [5] Xu Z, Jin Y, Gao Z, Zeng Y, et, al. Autophagic degradation of CCN2 (cellular communication network factor 2) causes cardiotoxicity of sunitinib. Autophagy. 2022 May;18(5):1152-1173. [6] Ghatalia P, Je Y, Mouallem NE, et al. Hepatotoxicity with vascular endothelial growth factor receptor tyrosine kinase inhibitors: A meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol. 2015 Mar;93(3):257-76. [7] Yan H, Wu W, Hu Y, et, al. Regorafenib inhibits EphA2 phosphorylation and leads to liver damage via the ERK/MDM2/p53 axis. Nat Commun. 2023 May 13;14(1):2756. [8] Du J, Yan H, Xu Z, et al. Cutaneous toxicity of FDA-approved small-molecule kinase inhibitors. Expert Opin Drug Metab Toxicol. 2021 Nov;17(11):1311-1325. [9] Jin Y, Chen X, Gao Z, et al. Bisdemethoxycurcumin alleviates vandetanib-induced cutaneous toxicity in vivo and in vitro through autophagy activation. Biomed Pharmacother. 2021 Dec; 144:112297. [10] Chanprapaph K, Rutnin S, Vachiramon V. Multikinase Inhibitor-Induced Hand-Foot Skin Reaction: A Review of Clinical Presentation, Pathogenesis, and Management. Am J Clin Dermatol. 2016 Aug;17(4):387-402. [11] Wang S, Yang Z, Wang Z. Are VEGFR-TKIs effective or safe for patients with advanced non-small cell lung cancer? Oncotarget. 2015 Jul 20;6(20):18206-23. [12] Shou L, Chen J, Shao T, et al. Clinical characteristics, treatment outcomes, and prognosis in patients with MKIs-associated hand-foot skin reaction: a retrospective study. Support Care Cancer. 2023 Jun 5;31(7):375. [13] Massey PR, Okman JS, Wilkerson J, et al. Tyrosine kinase inhibitors directed against the vascular endothelial growth factor receptor (VEGFR) have distinct cutaneous toxicity profiles: a meta-analysis and review of the literature. Support Care Cancer. 2015 Jun;23(6):1827-35. [14] Li J, Gu J. Hand-foot skin reaction with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: A systematic review and meta-analysis. Crit Rev Oncol Hematol. 2017 Nov;119: 50-58. [15] Luo P, Yan H, Chen X, et al. s-HBEGF/SIRT1 circuit-dictated crosstalk between vascular endothelial cells and keratinocytes mediates sorafenib-induced hand-foot skin reaction that can be reversed by nicotinamide. Cell Res. 2020 Sep;30(9):779-793. AOPWiki 2024-05-15T03:57:50

2024-05-26T20:40:00