Rao, C. N. | bioRxiv Science

bioRxiv2026

Lysyl oxidase drives ccRCC progression by coordinating HIF-2α transcription program with tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is driven by persistent HIF-2 transcription program initiated by VHL loss, yet molecular mediators sustaining this program are poorly defined. Using single-cell transcriptomics, we identified lysyl oxidase (LOX) as a driver of ccRCC progression, selectively enriched in a hypoxia/epithelial-mesenchymal transition (EMT) gene program associated with poor outcome. While LOX oxidizes and stabilizes HIF-2 by antagonizing HUWE1-mediated ubiquitination and degradation, thereby sustaining HIF-2-driven transcription in cancer cells, it also remodels extracellular matrix (ECM) and promotes angiogenesis in the tumor microenvironment (TME). Genetic or pharmacological inhibition of LOX destabilizes HIF-2, disrupts ECM, inhibits angiogenesis, and suppresses tumor initiation, growth, and metastasis in vivo. LOX inhibition enhances anti-angiogenic therapy response and remains effective in belzutifan-resistant HIF-2 G323E-mutant tumors. Nuclear LOX protein correlates with nuclear HIF-2 in high-grade patient tumors. Together, LOX coordinates HIF-2 transcription program with TME and is a therapeutic target in ccRCC.

cancer biology↗

bioRxiv2026

Abbapolin inhibitors of the PLK1 PBD as Prostate Cancer Therapeutics, in vivo activity and synergy with androgen therapy

Polo-like kinase 1 (PLK1) is an established therapeutic target in cancer; however, ATP-competitive kinase inhibitors have shown limited clinical success because of toxicity, acquired resistance, and incomplete inhibition of non-catalytic PLK1 functions. Targeting the Polo-box domain (PBD), which regulates PLK1 localization and substrate recognition, represents an alternative therapeutic strategy but has been hindered by the lack of selective, cell-active small molecules. Here, the optimization and biological characterization of abbapolins, a series of non-peptidic PLK1 PBD inhibitors developed using the REPLACE strategy are described. Structure-guided optimization and screening across the NCI-60 cancer cell panel identified compounds with preferential activity against prostate cancer cells. Proteomic analyses demonstrated that cellular sensitivity correlated with PLK1 protein abundance, supporting an on-target mechanism of action. Abbapolins directly engaged PLK1 in cells, induced selective degradation of endogenous PLK1, and suppressed long-term clonogenic growth. Lead compounds demonstrated favorable pharmacokinetic properties and significantly inhibited prostate tumor growth in xenograft models without detectable systemic toxicity. PLK1 abundance was significantly reduced in treated tumors and correlated with tumor response, identifying PLK1 degradation as a potential pharmacodynamic biomarker. Abbapolins also synergized with enzalutamide in castration- resistant prostate cancer cells, supporting their potential as combination therapies for advanced disease. Collectively, these studies establish selective inhibition of the PLK1 Polo-box domain as a viable therapeutic strategy, provide in vivo proof-of-concept for the REPLACE approach, and identify abbapolins as promising leads for advanced prostate cancer.

cancer biology↗