Hu Kuan, Xia Yu, Yuan Tong, Lin Yan, Yang Jin
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 211198, China.
Pharmaceutics. 2025 Aug 12;17(8):1044. doi: 10.3390/pharmaceutics17081044.
Combining pemetrexed (PEM) with Osimertinib (OSI) improves outcomes in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), but optimal scheduling remains undefined. Sequential PEM → OSI strategies may outperform concurrent administration; however, the critical dosing interval determining synergy has not been explored. : PEM pharmacodynamics were divided into an OSI-antagonized early phase (S-phase arrest and DNA damage accumulation) and OSI-synergized late phase (DNA damage peak, apoptosis initiation, and feedback EGFR activation). Time-course profiling of cell cycle, DNA damage, apoptosis, and EGFR pathways was evaluated under monotherapy or sequential combination regimens to elucidate the mechanisms underlying synergistic/antagonistic effects. OSI antagonizes PEM's early phase via G1 arrest but potently enhances late-phase apoptosis through Rad51/thymidylate synthase suppression, Bim upregulation, and inhibition of EGFR signaling. The 48 h interval PEM → OSI uniquely enabled complete early-phase execution and aligned OSI exposure with late-phase initiation, yielding robust synergy across OSI-sensitive cell lines. In contrast, the 24 h interval PEM → OSI sequence demonstrated synergy only in PEM-sensitive PC9 cells. Both concurrent PEM + OSI and OSI → PEM sequence induced attenuated DNA damage and apoptotic signaling. The 48 h interval PEM → OSI sequence maximizes efficacy by temporally segregating antagonistic and synergistic interactions. This pharmacodynamically optimized regimen represents a promising strategy for clinical translation.
培美曲塞（PEM）与奥希替尼（OSI）联合使用可改善表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）的治疗效果，但最佳给药方案仍未明确。序贯PEM→OSI策略可能优于同时给药；然而，尚未探索决定协同作用的关键给药间隔。PEM的药效学分为OSI拮抗的早期阶段（S期阻滞和DNA损伤积累）和OSI协同的晚期阶段（DNA损伤峰值、凋亡启动和反馈EGFR激活）。在单一疗法或序贯联合方案下评估细胞周期、DNA损伤、凋亡和EGFR通路的时间进程分析，以阐明协同/拮抗作用的潜在机制。OSI通过G1期阻滞拮抗PEM的早期阶段，但通过抑制Rad51/胸苷酸合成酶、上调Bim和抑制EGFR信号通路有力地增强晚期凋亡。48小时间隔的PEM→OSI能独特地实现早期阶段的完全执行，并使OSI暴露与晚期启动同步，在对OSI敏感的细胞系中产生强大的协同作用。相比之下，24小时间隔的PEM→OSI序列仅在对PEM敏感的PC9细胞中表现出协同作用。同时给予PEM+OSI和OSI→PEM序列均诱导DNA损伤和凋亡信号减弱。48小时间隔的PEM→OSI序列通过在时间上分离拮抗和协同相互作用使疗效最大化。这种药效学优化的方案代表了一种有前景的临床转化策略。
