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<p>KRAS mutations are prevalent in brain metastases (BM) from non-small cell lung cancer (NSCLC). The activity of KRAS-G12C selective, brain-penetrant small molecule inhibitor adagrasib was recently demonstrated in preclinical models of BM and patients with BM carrying KRAS-G12C, leading to a clinical trial investigating this therapeutic approach. However, co-existing genomic drivers such as homozygous deletion of <i>CDKN2A/B</i> may impact the utility of adagrasib. We therefore explored the combination therapy employing adagrasib and abemaciclib, a brain-penetrant CDK4/6 inhibitor, in NSCLC BM models driven by KRAS-G12C and <i>CDKN2A</i> loss. In both adagrasib-resistant SW1573 cells and adagrasib-responsive H2122 cells, combination of adagrasib and abemaciclib was slightly synergistic in inhibiting cell viability in vitro through targeting the KRAS-ERK and CDK4/6-Rb signaling pathways. Combination treatment was necessary to activate caspase 3/7-mediated apoptosis in SW1573 cells, while adagrasib alone and in combination comparably elicited apoptosis in H2122 cells. In vivo, combination treatment with adagrasib (75&#xa0;mg/kg) twice daily and abemaciclib (50&#xa0;mg/kg) daily was associated with body weight loss (about 10%) in mice bearing orthotopic BM derived with SW1573 or H2122 cells, requiring 50% dose reduction of adagrasib in some animals. Notably, combination treatment, but neither monotherapy, extended animal survival in the SW1573 model. On the other hand, adagrasib monotherapy and combination were similarly effective at prolonging survival, while abemaciclib monotherapy was ineffective in the H2122 model. Pharmacokinetic studies confirmed brain-penetrant properties of both agents and revealed drug-drug interactions as abemaciclib exposures in the plasma and brains were increased by the presence of adagrasib. Immunohistochemistry demonstrated on-target pharmacodynamic effects of both agents in BM in mice. Our work thus supports that the combination treatment of adagrasib and abemaciclib can offer a therapeutic strategy in NSCLC BM genomically characterized by KRAS-G12C and CDKN2A loss.</p>

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Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models genomically characterized by KRAS-G12C and homozygous loss of CDKN2A

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月2日

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  • Christian Migliarese,
  • Yinon Sadeh,
  • Consuelo Torrini,
  • Fatma Turna Demir,
  • Naema Nayyar,
  • Erika Yamazawa,
  • Yuu Ishikawa,
  • Nazanin Ijad,
  • Elizabeth J. Summers,
  • Adam Elliott,
  • Lisa Rahbaek,
  • Barbara Saechao,
  • Jill Hallin,
  • Priscilla K. Brastianos,
  • Hiroaki Wakimoto

摘要

KRAS mutations are prevalent in brain metastases (BM) from non-small cell lung cancer (NSCLC). The activity of KRAS-G12C selective, brain-penetrant small molecule inhibitor adagrasib was recently demonstrated in preclinical models of BM and patients with BM carrying KRAS-G12C, leading to a clinical trial investigating this therapeutic approach. However, co-existing genomic drivers such as homozygous deletion of CDKN2A/B may impact the utility of adagrasib. We therefore explored the combination therapy employing adagrasib and abemaciclib, a brain-penetrant CDK4/6 inhibitor, in NSCLC BM models driven by KRAS-G12C and CDKN2A loss. In both adagrasib-resistant SW1573 cells and adagrasib-responsive H2122 cells, combination of adagrasib and abemaciclib was slightly synergistic in inhibiting cell viability in vitro through targeting the KRAS-ERK and CDK4/6-Rb signaling pathways. Combination treatment was necessary to activate caspase 3/7-mediated apoptosis in SW1573 cells, while adagrasib alone and in combination comparably elicited apoptosis in H2122 cells. In vivo, combination treatment with adagrasib (75 mg/kg) twice daily and abemaciclib (50 mg/kg) daily was associated with body weight loss (about 10%) in mice bearing orthotopic BM derived with SW1573 or H2122 cells, requiring 50% dose reduction of adagrasib in some animals. Notably, combination treatment, but neither monotherapy, extended animal survival in the SW1573 model. On the other hand, adagrasib monotherapy and combination were similarly effective at prolonging survival, while abemaciclib monotherapy was ineffective in the H2122 model. Pharmacokinetic studies confirmed brain-penetrant properties of both agents and revealed drug-drug interactions as abemaciclib exposures in the plasma and brains were increased by the presence of adagrasib. Immunohistochemistry demonstrated on-target pharmacodynamic effects of both agents in BM in mice. Our work thus supports that the combination treatment of adagrasib and abemaciclib can offer a therapeutic strategy in NSCLC BM genomically characterized by KRAS-G12C and CDKN2A loss.