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We recently reported mutations in exons encoding the C-terminal tail of PTCH1 in colon cancer, which result in premature truncation but do not impair canonical Hedgehog signalling. In this study, we show that colon cancer cells engineered by CRISPR\/Cas9 to express endogenous truncated PTCH1 have enhanced proliferation, colony formation, anchorage-independent growth and form larger tumours in vivo than isogenic cells expressing wild-type PTCH1. Analysis of the mechanisms underlying this growth advantage revealed profound transcriptional changes and unexpectedly, upregulation of GLI1 and GLI2 by a Smoothened-independent route, which proved to be necessary for the proliferative advantage. Furthermore, we found that truncation of PTCH1 C-tail upregulated several cancer-related pathways, including EGFR and Ras signalling and led to enhanced GLI-dependent PI3K activation, which exerted a positive feedback regulation on GLI expression and activity. Accordingly, PTCH1 mutant cells were highly sensitive to PI3K and GLI inhibitors and were only partially sensitive to EGFR and MEK inhibitors. Altogether, these findings reveal that PTCH1 C-tail truncating mutations promote colon cancer tumourigenesis through a non-canonical GLI-PI3K positive loop.<\/jats:p>","DOI":"10.1038\/s41388-026-03698-9","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T08:47:20Z","timestamp":1772095640000},"page":"1013-1025","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Partial truncation of the C-terminal domain of PTCH1 in cancer promotes tumourigenesis by non-canonical activation of a GLI-PI3K loop"],"prefix":"10.1038","volume":"45","author":[{"given":"Bego\u00f1a","family":"Caballero-Ruiz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Bordone","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonia","family":"Coni","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danai S.","family":"Gkotsi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6694-2613","authenticated-orcid":false,"given":"Gianluca","family":"Canettieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8942-7873","authenticated-orcid":false,"given":"Natalia A.","family":"Riobo-Del Galdo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"3698_CR1","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/s41580-023-00591-1","volume":"24","author":"Y Zhang","year":"2023","unstructured":"Zhang Y, Beachy PA. 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