Androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are front-line treatments for highly aggressive prostate cancer. However, prolonged inhibition of AR triggers a compensatory activation of PI3K pathway, most often due to the genomic loss of tumor suppressor PTEN, driving progression to the castration-resistant prostate cancer (CRPC) stage, which has very poor prognosis. We uncovered a novel mechanism of PTEN downregulation triggered by LIMK2, which contributes significantly to CRPC pathogenesis. LIMK2 is a CRPC-specific target. Its depletion fully reverses tumorigenesis in vivo. LIMK2 phosphorylates PTEN at five sites, degrading and inhibiting its activity, thereby driving highly aggressive oncogenic phenotypes in cells and in vivo. PTEN also degrades LIMK2 in a feedback loop, which was confirmed in prostates from PTEN^−/− and PTEN^+/+ mice. LIMK2 is also the missing link between hypoxia and PTEN degradation in CRPC. This is the first study to show a feedback loop between PTEN and its regulator. Uncovering the LIMK2-PTEN loop provides a powerful therapeutic opportunity to retain the activity and stability of PTEN protein by inhibiting LIMK2, thereby halting the progression to CRPC, ADT-resistance and drug-resistance.

雄激素剥夺疗法 (ADT) 和雄激素受体 (AR) 信号抑制剂是高侵袭性前列腺癌的一线治疗方法。然而，长期抑制 AR 会触发 PI3K 通路的代偿性激活，最常见的原因是肿瘤抑制基因 PTEN 的基因组丢失，从而导致进展到去势抵抗性前列腺癌 (CRPC) 阶段，该阶段预后非常差。我们发现了一种由 LIMK2 触发的 PTEN 下调的新机制，这对 CRPC 发病机制有重要贡献。LIMK2 是 CRPC 特定的目标。它的消耗完全逆转了体内的肿瘤发生。LIMK2 在五个位点磷酸化 PTEN，降解和抑制其活性，从而在细胞和体内驱动高度侵袭性的致癌表型。PTEN 还会在反馈循环中降低 LIMK2，^-/-和 PTEN ^+/+小鼠。LIMK2 也是 CRPC 中缺氧和 PTEN 降解之间缺失的环节。这是第一项显示 PTEN 与其调节器之间的反馈回路的研究。揭示 LIMK2-PTEN 环提供了一个强大的治疗机会，通过抑制 LIMK2 来保持 PTEN 蛋白的活性和稳定性，从而阻止进展为 CRPC、ADT 抗性和药物抗性。