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Background <p>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.</p> Methods <p>This study employed in vitro, ex vivo, and in vivo experiments to evaluate the myeloid-protective effects of AU2–94 against chemotherapy-induced damage.</p> Results <p>AU2–94&#xa0;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.</p> Conclusion <p>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.</p> Graphical abstract <p>Schematic representation of the proposed mechanism by which AU2–94 preserves bone marrow cells from cisplatin-induced toxicity in RB-deficient cancer. (A) DNA-damaging chemotherapeutic drugs like cisplatin induce tumour cell death and provoke double-strand DNA damage in rapidly proliferating cells, including bone marrow (BM) cells, leading to unwanted myelosuppression. (B) Pre-administration of the selective CDK4 inhibitor AU2–94 before cisplatin induces transient G1 arrest in BM cells, a phase critical for monitoring DNA integrity. This intervention prevents chemotherapy-induced double-strand DNA damage in BM cells, thereby aiding in myelopreservation. Given that TNBC-derived tumour cells often carry genetic mutations in the retinoblastoma (RB) protein, these cells are resistant to CDK4 inhibition. Hence, the addition of AU2–94 to a cisplatin regimen does not interfere with treatment outcomes but solely functions as a myelopreservation strategy.</p>

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A novel CDK4 inhibitor for myeloid protection in chemotherapy-treated triple-negative breast Cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月6日

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  • Ava Safaroghli-azar,
  • Laychiluh B Mekonnen,
  • Ramin Hassankhani,
  • Jimma Lenjisa,
  • Sunita KC Basnet,
  • Hajer Batayneh,
  • Muhammed H Rahaman,
  • Shudong Wang

摘要

Background

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.

Methods

This study employed in vitro, ex vivo, and in vivo experiments to evaluate the myeloid-protective effects of AU2–94 against chemotherapy-induced damage.

Results

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.

Conclusion

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.

Graphical abstract

Schematic representation of the proposed mechanism by which AU2–94 preserves bone marrow cells from cisplatin-induced toxicity in RB-deficient cancer. (A) DNA-damaging chemotherapeutic drugs like cisplatin induce tumour cell death and provoke double-strand DNA damage in rapidly proliferating cells, including bone marrow (BM) cells, leading to unwanted myelosuppression. (B) Pre-administration of the selective CDK4 inhibitor AU2–94 before cisplatin induces transient G1 arrest in BM cells, a phase critical for monitoring DNA integrity. This intervention prevents chemotherapy-induced double-strand DNA damage in BM cells, thereby aiding in myelopreservation. Given that TNBC-derived tumour cells often carry genetic mutations in the retinoblastoma (RB) protein, these cells are resistant to CDK4 inhibition. Hence, the addition of AU2–94 to a cisplatin regimen does not interfere with treatment outcomes but solely functions as a myelopreservation strategy.