Department of Pathology and Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California 92093, USA.
School of Medicine, Division of Hematology/Oncology, University of California, San Diego, La Jolla, California 92093, USA.
Nat Cell Biol. 2014 May;16(5):457-68. doi: 10.1038/ncb2953. Epub 2014 Apr 20.
Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, α(v)β₃, in the unliganded state, recruits KRAS and RalB to the tumour cell plasma membrane, leading to the activation of TBK1 and NF-κB. In fact, α(v)β₃ expression and the resulting KRAS-RalB-NF-κB pathway were both necessary and sufficient for tumour initiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings not only identify α(v)β₃ as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.
肿瘤细胞具有干细胞样特性，具有很强的侵袭性，并且常常表现出耐药性。在这里，我们揭示整合素 α(v)β₃ 可作为具有干细胞样特性的乳腺癌、肺癌和胰腺癌的标志物，这些肿瘤对受体酪氨酸激酶抑制剂（如厄洛替尼）具有高度耐药性。这在体外、在携带患者来源的肿瘤异种移植的小鼠中以及在对厄洛替尼进展的肺癌患者的临床标本中都得到了观察。从机制上讲，未配体结合的 α(v)β₃ 将 KRAS 和 RalB 募集到肿瘤细胞膜上，导致 TBK1 和 NF-κB 的激活。事实上，α(v)β₃ 表达及其导致的 KRAS-RalB-NF-κB 通路对于肿瘤起始、锚定独立性、自我更新和厄洛替尼耐药性都是必需且充分的。用硼替佐米对该通路进行药理学靶向治疗可逆转肿瘤干细胞特性和厄洛替尼耐药性。这些发现不仅鉴定了 α(v)β₃ 作为癌干细胞标志物/驱动因子，还揭示了一种使此类肿瘤对 RTK 抑制敏感的治疗策略。
