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

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Seguin, Laetitia | Camargo, Maria | Wettersten, Hiromi | Kato, Shumei | Desgrosellier, Jay | von Schalscha, Tami | Elliott, Kathryn | Cosset, Erika | Lesperance, Jacqueline | Weis, Sara | Cheresh, David

Edité par CCSD ; American Association for Cancer Research -

International audience. 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.

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