| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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| Outline of Final Research Achievements |
ROR1 sustains prosurvival signaling directly downstream of the lineage-survival oncogene TTF-1 in lung adenocarcinoma. In this study, we report an unanticipated function of this receptor tyrosine kinase (RTK) as a scaffold of CAVIN1 and CAV1, two essential structural components of caveolae. This kinase-independent function of ROR1 facilitates the interactions of CAVIN1 and CAV1 at the plasma membrane, thereby preventing the lysosomal degradation of CAV1. Caveolae structures and prosurvival signaling towards AKT through multiple RTKs are consequently sustained. We also provide mechanistic insight into how ROR1 inhibition can overcome EGFR-tyrosine kinase inhibitor resistance due to bypass signaling 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 appears to be an attractive approach to better treating this devastating cancer.
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