The Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
AstraZeneca, Alderley Park, Macclesfield, UK.
Eur Urol. 2015 Jun;67(6):986-990. doi: 10.1016/j.eururo.2014.08.006. Epub 2014 Aug 20.
The phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt (PI3K/Akt) pathway is a key pathway activated in castrate-resistant prostate cancer (CRPC). This preclinical study evaluates targeting of Akt with AZD5363 alone and in combination with enzalutamide (ENZ) to prevent and delay resistance. Our results demonstrate AZD5363 has significant proapoptotic, antiproliferative activity as monotherapy in ENZ-resistant cell lines in vitro and significantly decreased tumour growth in ENZ-resistant xenograft. The combination of AZD5363 and ENZ showed synergistic decreases in cell proliferation and induced cell-cycle arrest and apoptosis in prostate cancer cell lines LNCaP and C4-2. Notably, the combination of AZD5363 and ENZ resulted in an impressive regression of castrate-resistant LNCaP xenograft tumours without any recurrence demonstrated, whereas progression occurred with both monotherapies. Serum prostate-specific antigen (PSA) levels were also continuously suppressed, and nadir PSA levels were lower in the combination arm compared to ENZ alone. Combination AZD5363 and ENZ at time of castration similarly resulted in significant regression of tumours, with greater relative suppression of PSA compared to when administered to castrate-resistant xenografts. In summary, combination AZD5363 and ENZ significantly delays the development of ENZ resistance in preclinical models through synergistic increases in apoptosis and cell cycle arrest. Our results also suggest greater efficacy may be seen with earlier combination treatment. This study provides preclinical data to support evaluation of combination targeting of the PI3K/Akt pathway and the androgen-receptor axis in the clinic using AZD5363 and ENZ, respectively.
Targeting of the Akt and androgen receptor pathways with AZD5363 and enzalutamide, respectively, significantly delayed the development of enzalutamide-resistant prostate cancer through increased apoptosis and cell cycle arrest. This preclinical synergy provides a strong rationale for clinical evaluation of this combination.
磷酸肌醇-4,5-二磷酸 3-激酶/蛋白激酶 B（PI3K/Akt）途径是在去势抵抗性前列腺癌（CRPC）中被激活的关键途径。这项临床前研究评估了 Akt 的靶向治疗，包括单独使用 AZD5363 以及与恩扎鲁胺（ENZ）联合使用，以预防和延迟耐药性的发生。我们的研究结果表明，AZD5363 作为单一药物在体外对恩扎鲁胺耐药细胞系具有显著的促凋亡、抗增殖活性，并且显著降低了恩扎鲁胺耐药异种移植瘤的肿瘤生长。AZD5363 与 ENZ 的联合使用显示出协同的细胞增殖抑制作用，并诱导前列腺癌细胞系 LNCaP 和 C4-2 的细胞周期停滞和凋亡。值得注意的是，AZD5363 与 ENZ 的联合使用导致去势抵抗的 LNCaP 异种移植瘤的显著消退，没有任何复发的迹象，而单独使用两种药物则会导致肿瘤进展。血清前列腺特异性抗原（PSA）水平也持续受到抑制，联合用药组的 PSA 最低值低于单独使用恩扎鲁胺组。在去势时联合使用 AZD5363 和 ENZ 也同样导致肿瘤的显著消退，与单独用于去势抵抗性异种移植瘤相比，PSA 的相对抑制作用更大。总之，AZD5363 和 ENZ 的联合使用通过协同增加细胞凋亡和细胞周期停滞，显著延迟了临床前模型中恩扎鲁胺耐药的发展。我们的研究结果还表明，早期联合治疗可能会产生更大的疗效。这项研究提供了临床前数据，支持分别使用 AZD5363 和恩扎鲁胺评估联合靶向治疗 PI3K/Akt 途径和雄激素受体轴在临床上的应用。
分别使用 AZD5363 和恩扎鲁胺靶向 Akt 和雄激素受体通路，通过增加细胞凋亡和细胞周期停滞，显著延迟了恩扎鲁胺耐药性前列腺癌的发展。这种临床前协同作用为该联合用药的临床评估提供了强有力的理论依据。
