Live-Cell Invasive Phenotyping Uncovers ALK2 as a Therapeutic Target in LKB1-Mutant Lung Cancer.

Autor:	Koo J; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia., Seong CS; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia., Parker RE; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.; Cancer Biology Graduate Program, Emory University, Atlanta, Georgia., Herrera A; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia., Dwivedi B; Biostatistics and Bioinformatics Shared Resource, Winship Cancer Institute of Emory University, Atlanta, Georgia., Arthur RA; Emory Integrated Computational Core, Emory University School of Medicine, Atlanta, Georgia., Dinasarapu AR; Department of Neurology, Emory University School of Medicine, Atlanta, Georgia., Johnston HR; Emory Integrated Computational Core, Emory University School of Medicine, Atlanta, Georgia., Claussen H; Emory Integrated Computational Core, Emory University School of Medicine, Atlanta, Georgia., Tucker-Burden C; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia., Ramalingam SS; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia., Fu H; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, Georgia., Zhou W; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia., Marcus AI; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia., Gilbert-Ross M; Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2024 Nov 15; Vol. 84 (22), pp. 3761-3771.
DOI:	10.1158/0008-5472.CAN-23-2631
Abstrakt:	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. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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