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<p>Aberrant cyclin-dependent kinase 2 (CDK2) activity is implicated as a resistance mechanism to CDK4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. Using preclinical patient-derived xenograft models, the CDK2i + CDK4/6i combination was active broadly across CDK4/6i-resistant and -naïve HR+ and triple-negative breast cancer models. A novel, weighted mRNA expression signature involving <i>CCND1</i>, <i>CCNE1</i>, <i>RB1</i>, and <i>CDKN2A</i> (p16) predicted response to combined inhibition of CDK2 and CDK4/6. Addition of endocrine therapy significantly enhanced antitumor activity in HR+ models, providing preclinical proof-of-concept for the broad antitumor activity of the triple combination. Early clinical data demonstrated activity of BLU-222, a potent and selective CDK2 inhibitor, both as monotherapy (<i>CCNE1</i> amplified) and in combination with ribociclib and fulvestrant in patients with HR+/HER2− breast cancer. These findings provide evidence that CDK2i combined with CDK4/6i can address multiple known mechanisms of resistance to CDK4/6i, enhancing antitumor responses in preclinical breast cancer models.</p>

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CDK2 inhibition enhances CDK4/6 inhibitor antitumor activity in comprehensive breast cancer PDX model screen

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月3日

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  • Nealia C. House,
  • Maxine M. Chen,
  • Sima Khazaei,
  • Victoria Brown,
  • Philip Ramsden,
  • David H. Peng,
  • Sydney Moore,
  • Liang Yuan,
  • Rentian Wu,
  • Fangyang Wang,
  • Linjie Luo,
  • Ningping Feng,
  • Christopher A. Bristow,
  • Timothy A. Yap,
  • Khandan Keyomarsi,
  • Joseph R. Marszalek,
  • Scott Ribich,
  • Mikael L. Rinne,
  • Lakshmi B. Muthuswamy,
  • Kerrie L. Faia

摘要

Aberrant cyclin-dependent kinase 2 (CDK2) activity is implicated as a resistance mechanism to CDK4/6 inhibitors (CDK4/6i) in hormone receptor–positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) breast cancer. Using preclinical patient-derived xenograft models, the CDK2i + CDK4/6i combination was active broadly across CDK4/6i-resistant and -naïve HR+ and triple-negative breast cancer models. A novel, weighted mRNA expression signature involving CCND1, CCNE1, RB1, and CDKN2A (p16) predicted response to combined inhibition of CDK2 and CDK4/6. Addition of endocrine therapy significantly enhanced antitumor activity in HR+ models, providing preclinical proof-of-concept for the broad antitumor activity of the triple combination. Early clinical data demonstrated activity of BLU-222, a potent and selective CDK2 inhibitor, both as monotherapy (CCNE1 amplified) and in combination with ribociclib and fulvestrant in patients with HR+/HER2− breast cancer. These findings provide evidence that CDK2i combined with CDK4/6i can address multiple known mechanisms of resistance to CDK4/6i, enhancing antitumor responses in preclinical breast cancer models.