Multikinase Inhibitors Induce Cutaneous Toxicity through OAT6-Mediated Uptake and MAP3K7-Driven Cell Death
Eric I Zimmerman1, Alice A Gibson2, Shuiying Hu2
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee.
Abstract:
The use of multikinase inhibitors (MKI) in oncology, such as sorafenib, is associated with a cutaneous adverse event called hand-foot skin reaction (HFSR), in which sites of pressure or friction become inflamed and painful, thus significantly impacting quality of life. The pathogenesis of MKI-induced HFSR is unknown, and the only available treatment options involve dose reduction or discontinuation of therapy, which have negative effects on primary disease management. To investigate the underlying mechanisms by which sorafenib promotes keratinocyte cytotoxicity and subsequent HFSR induction, we performed a transporter-directed RNAi screen in human epidermal keratinocytes and identified SLC22A20 (OAT6) as an uptake carrier of sorafenib. Further investigations into the intracellular mechanism of sorafenib activity through in situ kinome profiling identified the mitogen-activated protein kinase MAP3K7 (TAK1) as a target of sorafenib that induces cell death. Finally, we demonstrate that sorafenib induced keratinocyte injury in vivo and that this effect could be reversed by cotreatment with the OAT6 inhibitor probenecid. Collectively, our findings reveal a novel pathway that regulates the entry of some MKIs into keratinocytes and explains the basis underlying sorafenib-induced skin toxicity, with important implications for the therapeutic management of HFSR.
Insights
Multikinase inhibitors like sorafenib cause hand-foot skin reaction (HFSR) by entering skin cells via OAT6. Targeting this pathway may reduce sorafenib
Area of Science:
- Dermatology
- Oncology
- Pharmacology
Background:
- Multikinase inhibitors (MKIs), including sorafenib, are crucial cancer treatments.
- A common side effect is hand-foot skin reaction (HFSR), causing painful skin inflammation and reducing patient quality of life.
- Current management strategies for HFSR involve dose reduction or therapy cessation, negatively impacting cancer treatment efficacy.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying sorafenib-induced keratinocyte cytotoxicity and HFSR.
- To identify the specific transporter responsible for sorafenib uptake into keratinocytes.
- To explore intracellular targets of sorafenib that mediate cell death in skin cells.
Main Methods:
- Conducted a transporter-directed RNA interference (RNAi) screen in human epidermal keratinocytes.
- Utilized in situ kinome profiling to identify intracellular targets of sorafenib.
- Evaluated sorafenib-induced keratinocyte injury in vivo and assessed the effect of OAT6 inhibition.
Main Results:
- Identified SLC22A20 (OAT6) as the primary uptake carrier for sorafenib in keratinocytes.
- Determined that sorafenib targets MAP3K7 (TAK1), leading to keratinocyte cell death.
- Demonstrated that sorafenib causes in vivo keratinocyte injury, which is reversible with probenecid (an OAT6 inhibitor).
Conclusions:
- Revealed a novel pathway involving OAT6-mediated MKI entry into keratinocytes.
- Established the mechanism of sorafenib-induced skin toxicity, linking OAT6, TAK1, and keratinocyte death.
- Suggests OAT6 inhibition as a potential therapeutic strategy for managing MKI-induced HFSR.
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