Abstract 4585: ROR1 sustains caveolae and RTK-mediated survival signaling as a scaffold of cavin-1 and CAV1 in lung cancer

Abstract

Abstract TTF-1/NKX2-1, a homeobox-containing transcription factor indispensable for lung morphogenesis, was previously identified by four independent groups including us, as a “lineage-survival” oncogene involved in the pathogenesis of lung adenocarcinoma. We have further shown that TTF-1/NKX2-1 induces expression of the receptor tyrosine kinase-like orphan receptor 1 (ROR1), which in turn plays a “sustainer” role for EGFR-mediated signaling. Interestingly, ROR1 knockdown effectively overcame EGFR-TKI resistance-conferring, HGF-mediated bypass signaling through MET, suggesting that ROR1 sustains not only EGFR but also additional RTK signaling. However, the underlying mechanism remained rather elusive. We report here 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. Caveolae are 50-100 nm invaginations of the plasma membrane that play various physiological roles, including function as a platform for insulin-induced signaling in adipose tissue. We found that ROR1 facilitates the interactions of cavin-1 and CAV1 at the plasma membrane in a kinase-independent manner, thereby preventing the lysosomal degradation of CAV1, as well as consequential caveolae formation. Caveolae structures and prosurvival signaling towards AKT through multiple RTKs such as MET and IGF-IR are consequently sustained. The present findings thus provide mechanistic insight into how ROR1 inhibition can overcome EGFR-TKI resistance due to bypass signaling via diverse RTKs, which is currently a major clinical obstacle. Inhibition of prosurvival signaling and proliferation of lung cancer cells could be recapitulated by knocking down cavin-1 or CAV1, but they are unlikely to be suitable molecular targets for NSCLC treatment due to their crucial physiological functions in various organs even at low expression levels. In this regard, it should be noted that ROR1 is considered to be an onco-embryonic antigen with tumor-specific expression in adults. Taken together, development of novel therapeutic means to inhibit the scaffold function of ROR1 and thereby attack the cancer's “Achilles heel” is thus anticipated to be an attractive approach for improved treatment of this devastating cancer. Citation Format: Tomoya Yamaguchi, Can Lu, Lisa Ida, Kiyoshi Yanagisawa, Jiro Usukura, Jinglei Cheng, Naoe Hotta, Yukako Shimada, Hisanori Isomura, Motoshi Suzuki, Toyoshi Fujimoto, Takashi Takahashi. ROR1 sustains caveolae and RTK-mediated survival signaling as a scaffold of cavin-1 and CAV1 in lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4585.