Abstract Midkine (MDK), a heparin-binding growth factor, is aberrantly overexpressed in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), where it drives tumor progression, angiogenesis, EMT, and therapy resistance via PI3K/Akt, MAPK/ERK, and Notch pathways. Despite progress with low-dose computed tomography (LDCT) screening for lung cancer, high false-positive rates, cumulative radiation exposure, and suboptimal sensitivity are still major concerns. These limitations underscore the need for novel, noninvasive biomarkers to enhance early detection and guide the development of targeted therapies. Circulating MDK in serum and urine is a promising biomarker, and HBS-101, a first-in-class small-molecule inhibitor, selectively blocks MDK-receptor interactions and downstream oncogenic signaling, offering a biomarker-guided therapy.MDK expression was analyzed across tumor and normal tissues using The Cancer Genome Atlas Program (TCGA) and the Genotype-Tissue Expression (GTEx) data. Anti-tumor efficacy of HBS-101 was evaluated in vivo using an SW1573 NSCLC xenograft model treated intraperitoneally with HBS-101 (5 or 10 mg/kg) for 56 days and in vitro using a 3D SCLC organoid model (SB-17-54) across 0-200 µM to determine IC50 values. Tumor growth, body weight, systemic toxicity, and gene expression were monitored.RNA analyses revealed broad MDK overexpression in both NSCLC and SCLC, with significantly elevated levels in lung adenocarcinoma and squamous cell carcinoma compared to matched normal tissues. HBS-101 treatment led to a statistically significant dose-dependent tumor growth inhibition in NSCLC xenografts, reducing tumor volume by 55-60% compared to control (p0.01) without systemic toxicity. In SCLC organoids, HBS-101 demonstrated potent growth inhibition with an IC50 of 5.09 µM.Ongoing works include synthesizing fluorescent MDK derivatives and HBS-101 analogues to elucidate receptor interactions and enable high-throughput screening, and profiling MDK in EGFR-mutated NSCLC cell lines (PC-9, H1975) and their Osimertinib-resistant derivatives aim to define the MDK axis and its role in therapeutic resistance. Taken together, our findings validate MDK as both a circulating biomarker and a druggable target, and position HBS-101 as a promising candidate for precision lung cancer therapy. If validated, MDK inhibition could overcome EGFR-TKI resistance and enable MDK-based patient stratification, guiding next-generation inhibitors and early detection strategies. Citation Format: Roberto Borea, Francesco Drago, Malaak Sammour, Nigita Giovanni, Serena Li Zhao, Blake R. Peterson, Hareesh B. Nair, Christian Rolfo, Eswar Shankar. Targeting midkine-driven oncogenic signaling with HBS-101: A novel therapeutic strategy for lung cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4577.
Borea et al. (Fri,) studied this question.