title: RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors.
abstract: Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy, and the mechanisms of resistance remain poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively activation of the RAS-MAPK pathway circumvents Shh pathway dependency, drives tumor growth, and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation emerged from the antecedent BCC tumors. Together, these findings reveal a critical role of the RAS-MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.
authors.affiliation: Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Xuesong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts. University of Birmingham, Centre for Cardiovascular Sciences, College of Medical and Dental Sciences, Edgbaston, Birmingham, United Kingdom.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Ponomaryov
authors.affiliation: Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Ornell
authors.affiliation: Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhou
authors.affiliation: Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Sukriti K
authors.initials: SK
authors.lastname: Dabral
authors.affiliation: Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Pak
authors.affiliation: Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California.
authors.forename: Scott X
authors.initials: SX
authors.lastname: Atwood
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California.
authors.forename: Ramon J
authors.initials: RJ
authors.lastname: Whitson
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California.
authors.forename: Anne Lynn S
authors.initials: AL
authors.lastname: Chang
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California.
authors.forename: Jiang
authors.initials: J
authors.lastname: Li
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Oro
authors.affiliation: Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Chan
authors.affiliation: Novartis Institutes for Biomedical Research, Cambridge, Massachusetts.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Kelleher
authors.affiliation: Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts. rosalind_segal@dfci.harvard.edu.
authors.forename: Rosalind A
authors.initials: RA
authors.lastname: Segal
mesh_terms: D000813:Anilides / Q000008:administration & dosage; D000818:Animals; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000235:genetics*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics; D011725:Pyridines / Q000008:administration & dosage; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C509239:SHH protein, human; C491023:SMO protein, human; D000072086:Smoothened Receptor; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins