The receptor tyrosine kinase-like orphan receptor 1 (ROR1) sustains prosurvival signalling directly downstream of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinoma. Here we report an unanticipated function of this receptor tyrosine kinase (RTK) as a scaffold of cavin-1 and caveolin-1 (CAV1), two essential structural components of caveolae. This kinase-independent function of ROR1 facilitates the interactions of cavin-1 and CAV1 at the plasma membrane, thereby preventing the lysosomal degradation of CAV1. Caveolae structures and prosurvival signalling towards AKT through multiple RTKs are consequently sustained. These findings provide mechanistic insight into how ROR1 inhibition can overcome EGFR-tyrosine kinase inhibitor (TKI) resistance due to bypass signalling via diverse RTKs such as MET and IGF-IR, which is currently a major clinical obstacle. Considering its onco-embryonic expression, inhibition of the scaffold function of ROR1 in patients with lung adenocarcinoma is an attractive approach for improved treatment of this devastating cancer.

中文翻译：

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ROR1作为cavin-1和caveolin-1的支架维持caveolae和生存信号。

受体酪氨酸激酶样孤儿受体1（ROR1）在肺腺癌中直接在谱系生存癌基因NKX2-1 / TTF-1下游维持生存信号。在这里，我们报告这种受体酪氨酸激酶（RTK）的预期功能作为cavin-1和小窝蛋白1（CAV1）（小窝的两个基本结构组成部分）的支架。ROR1的这种与激酶无关的功能促进了cavin-1和CAV1在质膜上的相互作用，从而防止了CAV1的溶酶体降解。因此，通过多个RTK的小窝结构和向AKT的存活信号转导得以维持。这些发现为ROR1抑制如何克服MET-IGF-IR等多种RTK旁路信号导致的EGFR-酪氨酸激酶抑制剂（TKI）抗性提供了机械原理，这是目前的主要临床障碍。考虑到其癌胚表达，在肺腺癌患者中抑制ROR1的支​​架功能是改善该毁灭性癌症治疗的一种有吸引力的方法。