Abstract
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.
Highlights
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
We found that ROR1 functions as a scaffold protein of cavin-1 and CAV1, two essential structural components of caveolae, a function that in turn sustains caveolae formation and prosurvival signalling through multiple receptor tyrosine kinase (RTK) in non-small cell lung cancers (NSCLCs) cells
We further tested various growth factors, including IGF-I and -II, insulin and platelet-derived growth factor (PDGF) in NCI-H1975 cells (Fig. 1b), as well as IGF-I and -II, insulin and hepatocyte growth factor (HGF) in PC-9 cells (Supplementary Fig. 1b), and verified that the siROR1 treatment effectively inhibited growth factor-induced phosphorylation of RTKs and AKT. These findings led us to hypothesize that the inhibitory effects on the signalling of multiple RTKs may be caused by impairment of the caveolae structure; RTKs are in part localized in caveolae[4]
Summary
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. 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. Multiple mechanisms for EGFR–TKI resistance have been identified, including the secondary T790M EGFR mutation, as well as bypass signalling through other RTKs such as MET and insulin-like growth factor-I receptor (IGF-IR)[12,13]. Such resistance-conferring events may arise within the same tumour undergoing EGFR–TKI treatment[14], making it difficult to predict appropriate targets for the suppression and elimination of resistant clones. We found that ROR1 functions as a scaffold protein of cavin-1 and CAV1, two essential structural components of caveolae, a function that in turn sustains caveolae formation and prosurvival signalling through multiple RTKs in NSCLC cells
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