Bhoir Siddhant, De Benedetti Arrigo
Department of Biochemistry and Molecular Biology, LSU Health Shreveport, Shreveport, LA 71103, USA.
Department of Therapeutic Radiology, School of Medicine, Yale University, 15 York Street, New Haven, CT 06510, USA.
Cancers (Basel). 2024 Dec 29;17(1):75. doi: 10.3390/cancers17010075.
For nearly a century, fundamental observations that prostate cancer (PCa) cells nearly always require AR stimulation for sustained proliferation have led to a unidirectional quest to abrogate such a pathway. Similarly focused have been efforts to understand AR-driven processes in the context of elevated expression of its target genes, and much less so on products that become overexpressed when AR signaling is suppressed. Treatment with ARSI results in an increased expression of the TLK1B splice variant via a 'translational' derepression driven by the compensatory mTOR activation and consequent activation of the TLK1 > NEK1 > ATR > Chk1 and NEK1 > YAP axes. In due course, this results first in a pro-survival quiescence and then adaptation to ADT and CRPC progression. This constitutes a novel liability for PCa that we have targeted for several years and novel approaches.
近一个世纪以来，前列腺癌（PCa）细胞几乎总是需要雄激素受体（AR）刺激才能持续增殖这一基本观察结果，导致了人们对消除这一信号通路的单向探索。同样，人们致力于在AR靶基因表达升高的背景下理解AR驱动的过程，而对AR信号被抑制时过度表达的产物关注较少。使用雄激素受体信号抑制剂（ARSI）治疗会通过由代偿性mTOR激活以及随后TLK1 > NEK1 > ATR > Chk1和NEK1 > YAP轴的激活所驱动的“翻译”去抑制，导致TLK1B剪接变体的表达增加。随着时间的推移，这首先导致一种促生存的静止状态，然后导致对雄激素剥夺疗法（ADT）的适应和去势抵抗性前列腺癌（CRPC）进展。这构成了我们多年来一直针对的前列腺癌的一种新的易感性以及新的治疗方法。
