Abstract
Activating mutations in the Wnt pathway are a characteristic feature of colorectal cancer (CRC). The R-spondin (RSPO) family is a group of secreted proteins that enhance Wnt signaling and RSPO2 and RSPO3 gene fusions have been reported in CRC. We have previously shown that Wnt pathway blockers exhibit potent combinatorial activity with taxanes to inhibit tumor growth. Here we show that RSPO3 antagonism synergizes with paclitaxel based chemotherapies in patient-derived xenograft models (PDX) with RSPO3 fusions and in tumors with common CRC mutations such as APC, β-catenin, or RNF43. In these latter types of tumors that represent over 90% of CRC, RSPO3 is produced by stromal cells in the tumor microenvironment and the activating mutations appear to sensitize the tumors to Wnt-Rspo synergy. The combination of RSPO3 inhibition and taxane treatment provides an approach to effectively target oncogenic WNT signaling in a significant number of patients with colorectal and other intestinal cancers.
Highlights
Wnt pathway mutations that activate signaling are present in virtually all colorectal tumors, emphasizing the Wnt pathway as the fundamental oncogenic driver in this disease
We discovered that SNU1411 was highly sensitive to the combination of anti-RSPO3 and nab-paclitaxel even though it was resistant to anti-RSPO3 as a single agent or in combination with irinotecan (Fig. 1B)
We examined the efficacy of anti-Rspo[3] in combination with chemotherapy in ten colorectal cancer (CRC) patient-derived xenograft models (PDX) models
Summary
The experimental animal use protocols OMP3 and OMP6 relevant to these studies were approved by OncoMed IACUC committee Additional accreditation to this facility was provided by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). PDX tumor models were utilized in these studies. Preparation of PDX tumor samples for in vivo studies were as described[15]. The PCR primers for human and murine RSPO3 were determined to be species specific so that gene expression could be quantified in both tumor (human) and stromal (murine) cellular compartments using RNA prepared from xenograft tumors. Data for PDX tumor measurements are expressed as mean + S.E.M. and differences between groups were quantified with GraphPad Prism[7] using repeated measures two-way ANOVA with multiple planned comparisons
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