Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions

摘要

In colorectal cancer (CRC), WNT pathway activation by genetic rearrangements of RSPO3 is emerging as a promising target. However, its low prevalence severely limits availability of preclinical models for in‐depth characterization. Using a pipeline designed to suppress stroma‐derived signal, we find that RSPO3 “outlier” expression in CRC samples highlights translocation and fusion transcript expression. Outlier search in 151 CRC cell lines identified VACO6 and SNU1411 cells as carriers of, respectively, a canonical PTPRK(e1)‐RSPO3(e2) fusion and a novel PTPRK(e13)‐RSPO3(e2) fusion. Both lines displayed marked in vitro and in vivo sensitivity to WNT blockade by the porcupine inhibitor LGK974, associated with transcriptional and morphological evidence of WNT pathway suppression. Long‐term treatment of VACO6 cells with style="fixed-case">LGK974 led to the emergence of a resistant population carrying two frameshift deletions of the style="fixed-case">WNT pathway inhibitor style="fixed-case">AXIN1, with consequent protein loss. Suppression of style="fixed-case">AXIN1 in parental style="fixed-case">VACO6 cells by style="fixed-case">RNA interference conferred marked resistance to style="fixed-case">LGK974. These results provide the first mechanism of secondary resistance to style="fixed-case">WNT pathway inhibition.