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Cancer Discov. 2017 Dec;7(12):1464-1479. doi: 10.1158/2159-8290.CD-17-0539. Epub 2017 Sep 11.

Galectin-3, a Druggable Vulnerability for KRAS-Addicted Cancers.

Author information

1
Department of Pathology, Moores UCSD Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California. dcheresh@ucsd.edu lseguin@unice.fr.
2
Department of Pathology, Moores UCSD Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California.
3
School of Medicine, Division of Hematology/Oncology, University of California, San Diego, La Jolla, California.

Abstract

Identifying the molecular basis for cancer cell dependence on oncogenes such as KRAS can provide new opportunities to target these addictions. Here, we identify a novel role for the carbohydrate-binding protein galectin-3 as a lynchpin for KRAS dependence. By directly binding to the cell surface receptor integrin αvβ3, galectin-3 gives rise to KRAS addiction by enabling multiple functions of KRAS in anchorage-independent cells, including formation of macropinosomes that facilitate nutrient uptake and ability to maintain redox balance. Disrupting αvβ3/galectin-3 binding with a clinically active drug prevents their association with mutant KRAS, thereby suppressing macropinocytosis while increasing reactive oxygen species to eradicate αvβ3-expressing KRAS-mutant lung and pancreatic cancer patient-derived xenografts and spontaneous tumors in mice. Our work reveals galectin-3 as a druggable target for KRAS-addicted lung and pancreas cancers, and indicates integrin αvβ3 as a biomarker to identify susceptible tumors.Significance: There is a significant unmet need for therapies targeting KRAS-mutant cancers. Here, we identify integrin αvβ3 as a biomarker to identify mutant KRAS-addicted tumors that are highly sensitive to inhibition of galectin-3, a glycoprotein that binds to integrin αvβ3 to promote KRAS-mediated activation of AKT. Cancer Discov; 7(12); 1464-79. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 1355.

PMID:
28893801
PMCID:
PMC5718959
DOI:
10.1158/2159-8290.CD-17-0539
[Indexed for MEDLINE]
Free PMC Article

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