Department of Pathology, Moores UCSD Cancer Center, and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California.
School of Medicine, Division of Hematology/Oncology, University of California, San Diego, La Jolla, California.
Cancer Discov. 2017 Dec;7(12):1464-1479. doi: 10.1158/2159-8290.CD-17-0539. Epub 2017 Sep 11.
Identifying the molecular basis for cancer cell dependence on oncogenes such as 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 -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. There is a significant unmet need for therapies targeting -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. .
确定癌细胞对癌基因（如）的依赖性的分子基础，可以为靶向这些依赖性提供新的机会。在这里，我们发现了结合蛋白半乳糖凝集素-3作为 KRAS 依赖性的关键因素的新作用。通过直接结合细胞表面受体整合素αvβ3，半乳糖凝集素-3通过使 KRAS 在无锚定依赖性细胞中发挥多种功能，包括形成促进营养摄取的大胞饮泡和维持氧化还原平衡的能力，从而导致 KRAS 成瘾。用一种临床活性药物破坏αvβ3/半乳糖凝集素-3的结合，阻止它们与突变型 KRAS 结合，从而抑制大胞饮作用，同时增加活性氧物质以根除表达αvβ3的 -突变肺和胰腺癌细胞来源的异种移植物和小鼠中的自发肿瘤。我们的工作揭示了半乳糖凝集素-3是一种可用于治疗 KRAS 依赖性肺和胰腺癌症的药物靶点，并表明整合素αvβ3是识别易感肿瘤的生物标志物。针对 -突变癌症的治疗方法存在着巨大的未满足需求。在这里，我们确定整合素αvβ3是一种生物标志物，可识别对抑制半乳糖凝集素-3高度敏感的突变型 KRAS 依赖性肿瘤，半乳糖凝集素-3是一种与整合素αvβ3结合的糖蛋白，可促进 KRAS 介导的 AKT 激活。
