Targeting the AR-UBE2C axis unleashes autophagy-associated cell death to overcome intrinsic resistance to PI3K Inhibition in AR-overexpressed breast and prostate cancers

Abstract Luminal androgen receptor (LAR) subtype triple-negative breast cancer (TNBC) overexpresses AR, making anti-androgen receptor therapy a viable strategy. The PI3K/AKT/mTOR signaling pathway is a critical driver of tumorigenesis, yet intrinsic resistance mechanisms often compromise the clinical efficacy of PI3K inhibitors. In this study, we identified a novel isoflavone fluorinated derivative, compound 8, as a potential PI3K inhibitor. While compound 8 exhibited robust anti-tumor activity in AR-low triple-negative breast cancer cells (MDA-MB-231), AR-high cells (MDA-MB-453) displayed significant resistance. We demonstrated that high AR abundance blocks drug-induced autophagy-associated cell death and cell cycle arrest. Transcriptomic and functional analyses revealed that AR confers resistance by upregulating UBE2C. High levels of UBE2C not only sustained mitotic progression but also maintained autophagy inhibition, thereby limiting compound 8-induced autophagy-associated cytotoxicity. Importantly, we validated the universality of this mechanism in prostate cancer models using AR-high LNCaP cells and AR-low PC-3 cells. Genetic silencing of AR or pharmacological inhibition with Enz sensitized resistant cells to compound 8, enhancing cell-cycle arrest and promoting autophagy-associated cytotoxicity. Furthermore, the combination therapy synergistically suppressed tumor growth and metastasis in vivo. Collectively, our findings identify a novel PI3K inhibitor with potent inhibitory activity against both AR-low breast and prostate cancers, as well as elucidate a conserved AR-UBE2C-PI3K resistance axis across breast and prostate cancers, providing compelling preclinical rationale for combining PI3K inhibitors with anti-androgen therapy to overcome drug resistance.