Safaroghli-Azar Ava, Mekonnen Laychiluh B, Hassankhani Ramin, Lenjisa Jimma, Basnet Sunita Kc, Batayneh Hajer, Rahaman Muhammed H, Wang Shudong
Drug Discovery and Development, Clinical and Health Sciences, University of South Australia, Adelaide, South Australia, 5001, Australia.
Invest New Drugs. 2025 Jun 6. doi: 10.1007/s10637-025-01550-7.
Despite advances in cancer treatment, chemotherapy remains a cornerstone of clinical practice. However, its efficacy is often compromised by dose-limiting haematologic toxicities. Recent strategies aim to enhance chemotherapy tolerability while preserving its effectiveness. One emerging approach involves selective CDK4 inhibitors to serve as myeloid-protective agents in retinoblastoma (RB)-negative tumours, such as triple-negative breast cancer (TNBC). Because bone marrow (BM) cells rely on RB for proliferation, CDK4 inhibitors may protect these cells while sparing RB-deficient tumour cells. The present study investigated the potential of AU2-94, a first-in-class CDK4 inhibitor, to protect BM cells during myelosuppressive chemotherapy in TNBC, beyond its established application in RB-positive cancers.
This study employed in vitro, ex vivo, and in vivo experiments to evaluate the myeloid-protective effects of AU2-94 against chemotherapy-induced damage.
AU2-94 induced a transient G1 arrest that protects BM cells from chemotherapy-induced apoptosis by preventing DNA double-strand breaks. Pre-treatment with AU2-94 prior to 5-fluorouracil (5-FU) administration reduced BM cells apoptosis, preserved Ki67-positive cells, and mitigated declines in red blood cells and neutrophils. Similarly, AU2-94 pre-treatment before cisplatin administration reduced cisplatin-induced haematologic toxicity in RB-deficient TNBC bearing mice without compromising the efficacy of chemotherapy.
These findings support the repurposing of AU2-94 as a myeloprotective agent, highlighting its therapeutic potential in RB-deficient tumours. With AU2-94 advancing to clinical trials, these results underscore its broader therapeutic promise, extending to both RB-positive and RB-negative cancer treatment.
尽管癌症治疗取得了进展，但化疗仍然是临床实践的基石。然而，其疗效常常受到剂量限制性血液学毒性的影响。最近的策略旨在提高化疗耐受性的同时保持其有效性。一种新兴方法是使用选择性细胞周期蛋白依赖性激酶4（CDK4）抑制剂作为视网膜母细胞瘤（RB）阴性肿瘤（如三阴性乳腺癌（TNBC））的骨髓保护剂。由于骨髓（BM）细胞的增殖依赖于RB，CDK4抑制剂可能在保护这些细胞的同时使RB缺陷的肿瘤细胞不受影响。本研究调查了一流的CDK4抑制剂AU2-94在TNBC骨髓抑制化疗期间保护BM细胞的潜力，其应用范围超出了在RB阳性癌症中的既定应用。
本研究采用体外、离体和体内实验来评估AU2-94对化疗诱导损伤的骨髓保护作用。
AU2-94诱导短暂的G1期阻滞，通过防止DNA双链断裂保护BM细胞免受化疗诱导的凋亡。在给予5-氟尿嘧啶（5-FU）之前用AU2-94预处理可减少BM细胞凋亡，保留Ki67阳性细胞，并减轻红细胞和中性粒细胞的减少。同样，在给予顺铂之前用AU2-94预处理可降低顺铂诱导的RB缺陷型TNBC荷瘤小鼠的血液学毒性，而不影响化疗效果。
这些发现支持将AU2-94重新用作骨髓保护剂，突出了其在RB缺陷肿瘤中的治疗潜力。随着AU2-94进入临床试验，这些结果强调了其更广泛的治疗前景，延伸至RB阳性和RB阴性癌症治疗。
