ArticleJournal of advanced research2025
Cracking melanoma's armor: Supramolecular dual-strike on XPO1 and β-catenin to overcome resistance.
Article in Journal of advanced research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
introductionXPO1 plays a crucial role in the nuclear export machinery, making it an attractive target for inhibiting nuclear-cytoplasmic transport in melanoma, where its overexpression is linked to unfavorable prognosis. However, XPO1 monotherapy has not demonstrated sufficient efficacy to be considered a first-line treatment option for melanoma.
objectivesThis research aimed to delve into the resistance mechanism of XPO1-targeting therapy in melanoma and fabricate a proteinoid microsphere which could target XPO1 and β-catenin to maximize the effect of XPO1 inhibitors.
methodsTranscriptome sequencing was used to analyze the effects of XPO1 interference on the signaling pathways of melanoma. Nuclear-cytoplasmic protein separation, co-immunoprecipitation, and confocal microscopic analyses were conducted to clarify the resistance mechanism of XPO1 targeting therapy. A proteinoid microsphere named XPinβ was developed by co-assembling a specially designed XPO1 antagonistic peptide (XPin) and a β-catenin antagonist (Carnosic acid/CA). Cell model, mouse allograft and patient-derived xenograft (PDX) models were used to evaluate the antitumor effect of XPinβ.
resultsIn our study, inhibition of XPO1 led to the nuclear accumulation of β-catenin, altered the nuclear-cytoplasmic localization of APC, and activated the Wnt/β-catenin signaling pathway. XPinβ was efficiently internalized into melanoma cells via macropinocytosis, achieving simultaneous inhibition of both XPO1 and β-catenin. As expected, XPinβ demonstrated robust anti-tumor efficacy in an allograft melanoma mouse model, with significantly superior therapeutic effects compared to monotherapy targeting XPO1 or CA treatment alone. Moreover, XPinβ effectively inhibited growth of patient-derived xenograft (PDX) tumors overexpressing XPO1, outperforming both CA and the commercially available XPO1 inhibitor KPT-330. Most importantly, XPinβ significantly suppressed pulmonary metastasis of melanoma while maintaining excellent biosafety.
conclusionsThis study demonstrates the enhanced efficacy of XPO1-targeted therapy through the inhibition of the Wnt/β-catenin signaling pathway and introduces XPinβ, a proteinoid microsphere with promising clinical translational potential for dual targeting therapy against melanoma involving both XPO1 and β-catenin.
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