What is the clinical evidence from this study?

Study design: Other. Population: Non-small cell lung cancer (NSCLC). Intervention: ACF-01 and osimertinib vs. Either agent alone. Primary outcome: Tumor regression in HCC827 xenograft models.

What does this research mean for the field?

Co-administration of the novel PHD2 activator ACF-01 with osimertinib results in significantly greater tumor regression in NSCLC xenograft models than either agent alone by destabilizing HIF-1α. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.ESTABLISHES_NEW_DIRECTION.

What question did this study set out to answer?

The aim is to investigate the role of PHD2 activation in restoring sensitivity to EGFR-TKI therapy in NSCLC through HIF-1α destabilization.

May 20, 2026

B111-04 Prolyl Hydroxylase Domain Protein 2 (PHD2) Activation Restores Sensitivity to Epidermal Growth Factor Receptor (EGFR)-Tyrosine Kinase Inhibitor (TKI) Therapy by Destabilizing HIF-1α in NSCLC

Key Result

Co-administration of the PHD2 activator ACF-01 with osimertinib resulted in significantly greater tumor regression in NSCLC xenograft models than either agent alone.

Key Points

The aim is to investigate the role of PHD2 activation in restoring sensitivity to EGFR-TKI therapy in NSCLC through HIF-1α destabilization.
Developed ACF-01, a PHD2 activator, and evaluated its effects on HIF-1α in NSCLC cell lines.
Conducted in vitro assays for PHD2 binding and HIF-1α hydroxylation, alongside the Seahorse Glycolysis Stress Test.
Tested antitumor efficacy in HCC827 xenografts, assessing pharmacokinetics and toxicity in mice.
ACF-01 significantly enhanced HIF-1α degradation, suppressing glycolytic and angiogenic signaling.
In combination with osimertinib, ACF-01 markedly inhibited NSCLC cell growth and reduced ABC transporter-mediated drug efflux.
In vivo, co-treatment resulted in greater tumor regression compared to monotherapies, with reduced markers of proliferation.

Structured PICO

Does ACF-01 combined with osimertinib improve antitumor efficacy in NSCLC models?

Population

NSCLC cell lines with different EGFR backgrounds and HCC827 xenograft models in mice

Intervention

ACF-01 (a small-molecule PHD2 activator) co-administered with osimertinib

Comparator

Either agent alone (osimertinib or ACF-01)

Outcome

Antitumor efficacy (tumor regression) and cell growth inhibitionsurrogate

ACF-01, a novel PHD2 activator, enhances the antitumor efficacy of osimertinib in NSCLC models by destabilizing HIF-1α and disrupting metabolic adaptability.

Abstract

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).

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