ArticleCancer research2024
Live-Cell Invasive Phenotyping Uncovers ALK2 as a Therapeutic Target in LKB1-Mutant Lung Cancer.
Article in Cancer research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- LKB1 attenuates the transport activity of GLUT1 by regulating the alternative splicing of PKM1/PKM2 in cervical cancer.Journal of gynecologic oncology · 2026Article
- A patient-derived organoid model captures fetal-like plasticity in colorectal cancer.Cell research · 2025Article
- Targeting LKB1/STK11-mutant cancer: distinct metabolism, microenvironment, and therapeutic resistance.Trends in pharmacological sciences · 2025Review
- High PER1 expression is associated with STK11 mutation and clinical biomarkers of immunotherapy resistance in lung adenocarcinoma.Journal of cancer research and clinical oncology · 2025Article
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15 authors.
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Abstract
The acquisition of invasive properties is a prerequisite for tumor progression and metastasis. Molecular subtypes of KRAS-driven lung cancer exhibit distinct modes of invasion that contribute to unique growth properties and therapeutic susceptibilities. Despite this, preclinical strategies designed to exploit growth within the context of invasion are lacking. To address this, we designed an experimental system to screen for targetable signaling pathways linked to active early 3D invasion phenotypes in different molecular subtypes of KRAS-driven lung adenocarcinoma. Combined live-cell imaging of human bronchial epithelial cells in a 3D invasion matrix and transcriptomic profiling identified mutant LKB1-specific upregulation of BMP6. LKB1 loss increased BMP6 signaling, which induced the canonical iron regulatory hormone hepcidin. Intact LKB1 was necessary to maintain BMP6 signaling homeostasis and restrict ALK2/BMP6-fueled growth. Preclinical studies in a Kras/Lkb1-mutant syngeneic mouse model and in a xenograft model showed potent growth suppression by inhibiting the ALK2/BMP6 signaling axis with single-agent inhibitors that are currently in clinical trials. Lastly, BMP6 expression was elevated in tumors of patients with LKB1-mutant early-stage lung cancer. These results are consistent with those of a model in which LKB1 acts as a "brake" to iron-regulated growth and suggest that ALK2 inhibition can be used for patients with LKB1-mutant tumors. Significance: Three-dimensional invasion-linked gene expression analysis reveals a therapeutic vulnerability to inhibition of ALK2/BMP6 signaling in LKB1-mutant lung cancer that can be rapidly translated to the clinic.
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