期刊
MOLECULAR IMAGING AND BIOLOGY
卷 24, 期 3, 页码 498-509出版社
SPRINGER
DOI: 10.1007/s11307-021-01689-8
关键词
RAS-mutant; Macropinocytosis; Albumin; ARS-1620; NIR fluorescence; Lung cancer; Pancreatic cancer; Dextran
资金
- NCI Cancer Center Support Grant [P30 CA016672]
- NIH [P50 CA94056]
- Gerald Dewey Dodd, Jr., Endowed Distinguished Chair of the University of Texas MD Anderson Cancer Center
- Ruth L. Kirchstein Postdoctoral Individual Research Service Award (F32) NCI [F32CA250323]
- Harold C. and Mary L. Dailey Endowed Fellowship Recognition of Research Excellence (M.D. Anderson Cancer Center)
- Diane Denson Tobola Endowed Fellowship in Ovarian Cancer Research (M.D. Anderson Cancer Center)
Macropinocytosis is a critical mechanism for RAS-transformed cells to transport extracellular proteins, and inhibiting K-RAS activity or macropinocytosis can reduce albumin uptake. In vivo tumor retention of AF790-albumin is dependent on RAS inhibition and can be abrogated by macropinocytosis inhibition.
Purpose Macropinocytosis serves as a highly conserved endocytotic process that has recently been shown as a critical mechanism by which RAS-transformed cells transport extracellular protein into intracellular amino acid pathways to support their unique metabolic needs. We developed NIR fluorescently labeled molecular imaging probes to monitor macropinocytosis-mediated uptake of albumin in a K-RAS-dependent manner. Procedures Using western blot analysis, immunofluorescence, and flow cytometry, albumin retention was characterized in vitro across several RAS-activated lung and pancreatic cancer cell lines. AF790-albumin was synthesized and administered to mice bearing K-RAS mutant xenograft tumors of H460 (K-RAS p.Q61H) and H358 (K-RAS p.G12C) non-small cell lung cancers on each flank. Mice were treated daily with 2 mg/kg of ARS-1620, a targeted RAS p.G12C inhibitor, for 2 days and imaged following each treatment. Subsequently, the mice were then treated daily with 10 mg/kg of amiloride, a general inhibitor of macropinocytosis, for 2 days and imaged. Intratumoral distribution of AF790-albumin was assessed in vivo using near-infrared (NIR) fluorescence imaging. Results Albumin retention was observed as a function of K-RAS activity and macropinocytosis across several lung and pancreatic cancer cell lines. We documented that ARS-1620-induced inhibition of K-RAS activity or amiloride-mediated inhibition of macropinocytosis significantly reduced albumin uptake. Tumor retention in vivo of AF790-albumin was both RAS inhibition-dependent as well as abrogated by inhibition of macropinocytosis. Conclusions These data provide a novel approach using NIR-labeled human serum albumin to identify and monitor RAS-driven tumors as well as evaluate the on-target efficacy in vivo of inhibitors, such as ARS-1620.
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