{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T07:35:05Z","timestamp":1769067305542,"version":"3.49.0"},"reference-count":16,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T00:00:00Z","timestamp":1766275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["RC2025"],"award-info":[{"award-number":["RC2025"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Basal cell carcinoma (BCC) is the most common skin cancer, predominantly affecting sun-exposed areas. It typically grows slowly and rarely metastasizes, though untreated cases can cause significant tissue destruction and morbidity. Its pathogenesis primarily involves dysregulation of the Hedgehog (HH) signaling pathway, mainly through mutations in PTCH1 or SMO genes, leading to chronic activation of downstream GLI transcription factors. Accordingly, current targeted therapies for locally advanced, unresectable, or metastatic BCC focus on SMO inhibition, using orally administered drugs such as vismodegib and sonidegib. Although these therapies have shown success, many patients develop resistance, with about 50% harboring mutated SMO. In numerous cases, genetic determinants (sometimes pre-existing) of resistance remain unidentified, complicating patient management. Here, we report a case of a 58-year-old female with advanced BCC who initially exhibited a favorable response to sonidegib but developed resistance after approximately one year. This resistance was not attributable to the acquired mutations in SMO but rather to intra-tumor heterogeneity and additional mutations in critical driver genes, including TP53, APC, FGFR1 and NOTCH1, which likely enable HH pathway inhibition. To our knowledge, this is the first report documenting a sonidegib resistance mechanism in BCC that is independent of HH pathway mutations. This case highlights the complexity of resistance mechanisms to HH inhibitors and underscores the critical need for comprehensive molecular tumor profiling prior to initiating targeted therapy.<\/jats:p>","DOI":"10.3390\/ijms27010068","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:22:27Z","timestamp":1766578947000},"page":"68","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Resistance to SMO Inhibitors in Advanced Basal Cell Carcinoma: A Case Highlighting the Role of Molecular Tumor Profiling"],"prefix":"10.3390","volume":"27","author":[{"given":"Federica","family":"Papaccio","sequence":"first","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6640-7418","authenticated-orcid":false,"given":"Ramona","family":"Marrapodi","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Eibenschutz","sequence":"additional","affiliation":[{"name":"Oncologic and Preventative Dermatology, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0669-1442","authenticated-orcid":false,"given":"Andrea","family":"D\u2019Arino","sequence":"additional","affiliation":[{"name":"Oncologic and Preventative Dermatology, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Caputo","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alberto","family":"Marini","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simona","family":"Scano","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4108-3104","authenticated-orcid":false,"given":"Arianna","family":"Presaghi","sequence":"additional","affiliation":[{"name":"Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Cota","sequence":"additional","affiliation":[{"name":"Genetic Research, Molecular Biology and Dermatopathology Unit, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4908-5271","authenticated-orcid":false,"given":"Elisa","family":"Melucci","sequence":"additional","affiliation":[{"name":"Department of Pathology, Regina Elena National Cancer Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5192-5917","authenticated-orcid":false,"given":"Stefano","family":"Scalera","sequence":"additional","affiliation":[{"name":"Biostatistics, Bioinformatics and Clinical Trial Center, Regina Elena National Cancer Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5316-8937","authenticated-orcid":false,"given":"Emilia","family":"Migliano","sequence":"additional","affiliation":[{"name":"Department of Plastic and Regenerative Surgery, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marcello","family":"Maugeri-Sacc\u00e0","sequence":"additional","affiliation":[{"name":"Biostatistics, Bioinformatics and Clinical Trial Center, Regina Elena National Cancer Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pasquale","family":"Frascione","sequence":"additional","affiliation":[{"name":"Oncologic and Preventative Dermatology, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3883-5500","authenticated-orcid":false,"given":"Barbara","family":"Bellei","sequence":"additional","affiliation":[{"name":"Laboratory of Cutaneous Physiopathology and Integrated Center of Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Via Elio Chianesi 53, 00144 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1056\/NEJMra044151","article-title":"Basal-Cell 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Carcinog."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2165\/00128071-200910020-00001","article-title":"Clinical Implications of Aging Skin: Cutaneous Disorders in the Elderly","volume":"10","author":"Farage","year":"2009","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1080\/1061186X.2025.2496470","article-title":"Hedgehog Signalling Pathway Inhibitors in the Treatment of Basal Cell Carcinoma: An Updated Review","volume":"33","author":"Glibo","year":"2025","journal-title":"J. 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