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.

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确定癌细胞对癌基因（如KRAS）的依赖的分子基础可以为靶向这些成瘾提供新的机会。在这里，我们确定了碳水化合物结合蛋白galectin-3作为KRAS依赖的关键。通过直接结合细胞表面受体整联蛋白αvβ3，galectin-3通过在不依赖锚定的细胞中启用KRAS的多种功能，包括形成促进营养摄取和维持氧化还原平衡的大粒体，从而引起KRAS成瘾。破坏具有临床活性药物的αvβ3/ galectin-3结合可防止其与突变KRAS缔合，从而抑制巨噬细胞增多，同时增加活性氧以消除表达αvβ3的KRAS突变的肺癌和胰腺癌患者来源的异种移植物和小鼠自发性肿瘤。我们的工作表明，galectin-3是KRAS上瘾的肺癌和胰腺癌的可治疗靶标，并表明整联蛋白αvβ3是识别易感肿瘤的生物标志物。

启示：迫切需要针对KRAS突变癌症的疗法。在这里，我们将整联蛋白αvβ3鉴定为生物标志物，以鉴定对抑制galectin-3高度敏感的突变型KRAS上瘾的肿瘤，galectin-3是一种与整联蛋白αvβ3结合以促进KRAS介导的AKT活化的糖蛋白。巨蟹座Discov; 7（12）；1464–79。©2017 AACR。

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