Abstract
Cancers are driven by a variety of somatic gene mutations and identifying these mutations enables the development of novel target drugs. We have sought to identify abnormalities in Wnt pathway-related genes that are sensitive to Wnt inhibitor treatment. We examined Patient Derived Xenograft (PDX) RNA samples and found new R-Spondin 2 (RSPO2) transcript fusions with the EMC2, PVT1 or HNF4G genes. These fusion events were identified in about 1.4% of the digestive system cancer samples. We then examined the oncogenic effects of the RSPO2-EMC2 fusion gene and confirmed that it can drive oncogenesis, sustain tumor growth and promote metastasis. Finally, we used a Wnt pathway Porcupine inhibitor CGX1321 to treat PDX mouse models containing RSPO2 fusion genes. All the RSPO2 fusion tumors responded to the treatment and stopped progression. Our data show that Wnt pathway inhibition could provide an effective treatment for cancers containing RSPO2 fusion. The RSPO2 fusion will serve as a good biomarker for screening patients to support clinical treatment of digestive system cancers using Wnt pathway inhibitors.
Highlights
We analyzed various types of R-Spondin 2 (RSPO2) fusions in Patient Derived Xenograft (PDX) tumors and confirmed their driving effects in tumor progression
Most anti-tumor strategies targeting the Wnt pathway are focused on gene mutations that contribute to the formation or development of tumors
In a LGK794 pre-clinical study, scientists discovered that mutations of RNF43 in pancreatic ductal cancer confer Wnt dependency and sensitivity to LGK794 treatment[35]
Summary
We examined Patient Derived Xenograft (PDX) RNA samples and found new R-Spondin 2 (RSPO2) transcript fusions with the EMC2, PVT1 or HNF4G genes These fusion events were identified in about 1.4% of the digestive system cancer samples. Β-catenin translocates to the nucleus and docks at the TCF/LEF-binding sites to activate downstream gene expression[11,12] Such activation requires multiple protein complexation, which includes the Wnt ligand as well as[13,14], Frizzled[15] and RNF4316. Treatment of RSPO2 fusion tumors in vivo with a Wnt inhibitor resulted in growth inhibition These results indicate that RSPO2 fusions may serve as a good biomarker for patient selection in gastric and colon cancers that are dependent on the canonical Wnt pathway[27]
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