Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions
Abstract 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,...
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-01-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.201606773 |
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| author | Gabriele Picco Consalvo Petti Alessia Centonze Erica Torchiaro Giovanni Crisafulli Luca Novara Andrea Acquaviva Alberto Bardelli Enzo Medico |
| author_facet | Gabriele Picco Consalvo Petti Alessia Centonze Erica Torchiaro Giovanni Crisafulli Luca Novara Andrea Acquaviva Alberto Bardelli Enzo Medico |
| author_sort | Gabriele Picco |
| collection | DOAJ |
| description | Abstract 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 LGK974 led to the emergence of a resistant population carrying two frameshift deletions of the WNT pathway inhibitor AXIN1, with consequent protein loss. Suppression of AXIN1 in parental VACO6 cells by RNA interference conferred marked resistance to LGK974. These results provide the first mechanism of secondary resistance to WNT pathway inhibition. |
| format | Article |
| id | doaj-art-a44c8d397cc74b11b8277afa65862329 |
| institution | OA Journals |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-a44c8d397cc74b11b8277afa658623292025-08-20T02:11:18ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-01-019329330310.15252/emmm.201606773Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusionsGabriele Picco0Consalvo Petti1Alessia Centonze2Erica Torchiaro3Giovanni Crisafulli4Luca Novara5Andrea Acquaviva6Alberto Bardelli7Enzo Medico8Candiolo Cancer Institute – FPO IRCCSCandiolo Cancer Institute – FPO IRCCSDepartment of Oncology, University of TorinoCandiolo Cancer Institute – FPO IRCCSCandiolo Cancer Institute – FPO IRCCSCandiolo Cancer Institute – FPO IRCCSDepartment of Computer and Control Engineering, Politecnico di TorinoCandiolo Cancer Institute – FPO IRCCSCandiolo Cancer Institute – FPO IRCCSAbstract 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 LGK974 led to the emergence of a resistant population carrying two frameshift deletions of the WNT pathway inhibitor AXIN1, with consequent protein loss. Suppression of AXIN1 in parental VACO6 cells by RNA interference conferred marked resistance to LGK974. These results provide the first mechanism of secondary resistance to WNT pathway inhibition.https://doi.org/10.15252/emmm.201606773colorectal cancergene fusionR‐spondintargeted therapyWNT pathway |
| spellingShingle | Gabriele Picco Consalvo Petti Alessia Centonze Erica Torchiaro Giovanni Crisafulli Luca Novara Andrea Acquaviva Alberto Bardelli Enzo Medico Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions EMBO Molecular Medicine colorectal cancer gene fusion R‐spondin targeted therapy WNT pathway |
| title | Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions |
| title_full | Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions |
| title_fullStr | Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions |
| title_full_unstemmed | Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions |
| title_short | Loss of AXIN1 drives acquired resistance to WNT pathway blockade in colorectal cancer cells carrying RSPO3 fusions |
| title_sort | loss of axin1 drives acquired resistance to wnt pathway blockade in colorectal cancer cells carrying rspo3 fusions |
| topic | colorectal cancer gene fusion R‐spondin targeted therapy WNT pathway |
| url | https://doi.org/10.15252/emmm.201606773 |
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