Co-administration of the PHD2 activator ACF-01 with osimertinib resulted in significantly greater tumor regression in NSCLC xenograft models than either agent alone.
Does ACF-01 combined with osimertinib improve antitumor efficacy in NSCLC models?
ACF-01, a novel PHD2 activator, enhances the antitumor efficacy of osimertinib in NSCLC models by destabilizing HIF-1α and disrupting metabolic adaptability.
Abstract Rationale Hypoxia-induced stabilization of hypoxia-inducible factor-1α (HIF-1α) drives metabolic adaptation and therapeutic resistance in non-small cell lung cancer (NSCLC), particularly mediating EGFR-TKI failure through EGFR-independent pathways. Pharmacological approaches directly targeting HIF-1α have not achieved clinical success. We developed ACF-01, a first-in-class small-molecule PHD2 activator designed to enhance HIF-1α hydroxylation and proteasomal degradation, thereby restoring sensitivity to EGFR-TKI treatment under hypoxic conditions. Methods We evaluated direct PHD2 binding using surface plasmon resonance and HIF-1α hydroxylation via in vitro enzymatic assays. NSCLC cell lines with different EGFR backgrounds were analyzed for proliferation, apoptosis, metabolic reprogramming, and drug efflux. Extracellular acidification rate was assessed using the Seahorse Glycolysis Stress Test. Antitumor efficacy was tested in HCC827 xenograft models. Pharmacokinetic and toxicological profiles were assessed in mice to determine developability. Results ACF-01 directly bound PHD2 and enhanced hydroxylation-dependent degradation of HIF-1α, significantly suppressing downstream glycolytic and angiogenic signaling. ACF-01 synergized with osimertinib to markedly inhibit NSCLC cell growth, inducing S-phase arrest and apoptosis. Combination treatment also reduced ABC transporter-mediated drug efflux, supporting improved intracellular drug retention. In vivo, co-administration of ACF-01 with osimertinib resulted in significantly greater tumor regression than either agent alone, with concomitant reductions in proliferation and HIF-1α-associated markers. Importantly, ACF-01 demonstrated high metabolic stability and a wide safety margin without cardiotoxic or systemic toxic effects, highlighting favorable translational potential. Conclusions PHD2 activation represents a novel and mechanistically rational therapeutic strategy to overcome hypoxia-driven EGFR-independent resistance in NSCLC. ACF-01 effectively enhances osimertinib antitumor efficacy by destabilizing HIF-1α and disrupting metabolic adaptability. These findings support further development of ACF-01 as a combination partner for EGFR-TKI therapy to improve treatment durability in NSCLC. This abstract is funded by: This work was supported by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (RS-2025-21212975).
Cho et al. (Fri,) conducted a other in Non-small cell lung cancer (NSCLC). ACF-01 and osimertinib vs. Either agent alone was evaluated on Tumor regression in HCC827 xenograft models. Co-administration of the PHD2 activator ACF-01 with osimertinib resulted in significantly greater tumor regression in NSCLC xenograft models than either agent alone.