USP20 governs tyrosine kinase inhibitors resistance through ferroptosis evasion by targeting GPX4 in cancers

TL;DR

This study shows that USP20 helps cancer cells resist tyrosine kinase inhibitors by preventing ferroptosis, offering a new approach to treat resistant kidney and lung cancers.

Contribution

The paper identifies USP20 as a novel resistance driver that targets GPX4 to enable ferroptosis evasion in TKI-resistant cancers.

Findings

USP20 deubiquitinates GPX4, preventing its degradation and promoting resistance to TKIs.

Genetic or pharmacological inhibition of USP20 resensitizes resistant tumors to TKIs in vivo.

USP20 and GPX4 co-overexpression in patients correlates with poor prognosis in RCC and LC.

Abstract

Tyrosine kinase inhibitors (TKIs) including sunitinib and sorafenib remain first-line therapies for advanced renal cell carcinoma (RCC) and lung cancer (LC), but their efficacy is limited by acquired resistance. By characterizing metabolic adaptations in TKI-resistant tumors, we identify ubiquitin-specific peptidase 20 (USP20) as a critical resistance driver that enables cancer cells to evade ferroptosis. We demonstrate TKI-resistant cells upregulate USP20, which binds and deubiquitinates the ferroptosis suppressor GPX4, preventing its proteasomal degradation. Clinically, USP20 and GPX4 are co-overexpressed in RCC and LC patients, correlating with poor prognosis. Mechanistically, USP20 removes K48-linked polyubiquitination on GPX4, sustaining cellular antioxidant capacity. Genetic USP20 ablation sensitizes resistant tumors to TKI-induced ferroptosis. Pharmacological inhibition of USP20 was found to resensitize TKI-resistant tumors to sorafenib, resulting in marked suppression of tumor growth in vivo. Our work uncovers the USP20-GPX4 axis as a druggable linchpin of TKI resistance, revealing ferroptosis evasion as a metabolic vulnerability and proposing a new therapeutic paradigm for overcoming TKI tolerance in RCC and LC.

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