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.

ABSTRACT: 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

SUBMITTER: Migliarese C 

PROVIDER: S-EPMC12046717 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature