PMID- 26130651 OWN - NLM STAT- MEDLINE DCOM- 20151125 LR - 20190626 IS - 1538-7445 (Electronic) IS - 0008-5472 (Print) IS - 0008-5472 (Linking) VI - 75 IP - 17 DP - 2015 Sep 1 TI - RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. PG - 3623-35 LID - 10.1158/0008-5472.CAN-14-2999-T [doi] AB - 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. CI - (c)2015 American Association for Cancer Research. FAU - Zhao, Xuesong AU - Zhao X AD - Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts. FAU - Ponomaryov, Tatyana AU - Ponomaryov T AD - 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. FAU - Ornell, Kimberly J AU - Ornell KJ AD - Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts. FAU - Zhou, Pengcheng AU - Zhou P AD - Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts. FAU - Dabral, Sukriti K AU - Dabral SK AD - Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts. FAU - Pak, Ekaterina AU - Pak E AD - Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts. FAU - Li, Wei AU - Li W AD - Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard School of Public Health, Boston, Massachusetts. FAU - Atwood, Scott X AU - Atwood SX AD - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California. FAU - Whitson, Ramon J AU - Whitson RJ AD - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California. FAU - Chang, Anne Lynn S AU - Chang AL AD - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California. FAU - Li, Jiang AU - Li J AD - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California. FAU - Oro, Anthony E AU - Oro AE AD - Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California. FAU - Chan, Jennifer A AU - Chan JA AD - Pathology and Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada. FAU - Kelleher, Joseph F AU - Kelleher JF AD - Novartis Institutes for Biomedical Research, Cambridge, Massachusetts. FAU - Segal, Rosalind A AU - Segal RA AD - Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Neurobiology, Harvard Medical School, Boston, Massachusetts. rosalind_segal@dfci.harvard.edu. LA - eng GR - R01 AR054780/AR/NIAMS NIH HHS/United States GR - ARO4786/PHS HHS/United States GR - P01 CA142536/CA/NCI NIH HHS/United States GR - CA142536/CA/NCI NIH HHS/United States GR - R00 CA176847/CA/NCI NIH HHS/United States GR - R01 HG004069/HG/NHGRI NIH HHS/United States GR - R01 AR046786/AR/NIAMS NIH HHS/United States GR - K99 CA176847/CA/NCI NIH HHS/United States GR - HG4069/HG/NHGRI NIH HHS/United States GR - 5ARO54780/PHS HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20150630 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Anilides) RN - 0 (Hedgehog Proteins) RN - 0 (HhAntag691) RN - 0 (Pyridines) RN - 0 (Receptors, G-Protein-Coupled) RN - 0 (SHH protein, human) RN - 0 (SMO protein, human) RN - 0 (Smoothened Receptor) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 3.6.5.2 (ras Proteins) SB - IM MH - Anilides/administration & dosage MH - Animals MH - Carcinoma, Basal Cell/drug therapy/*genetics/pathology MH - Cell Proliferation/drug effects MH - Drug Resistance, Neoplasm/genetics MH - Gene Expression Regulation, Neoplastic/drug effects MH - Hedgehog Proteins/*genetics MH - Humans MH - Medulloblastoma/drug therapy/*genetics/pathology MH - Mice MH - Mitogen-Activated Protein Kinase Kinases/genetics MH - Pyridines/administration & dosage MH - Receptors, G-Protein-Coupled/antagonists & inhibitors/*biosynthesis MH - Signal Transduction/drug effects MH - Smoothened Receptor MH - Xenograft Model Antitumor Assays MH - ras Proteins/biosynthesis/*genetics PMC - PMC4558230 MID - NIHMS705357 COIS- COMPETING FINANCIAL INTERESTS JFK is a Novartis employee. AEO and AC are clinical investigators for Genentech and Novartis. EDAT- 2015/07/02 06:00 MHDA- 2015/12/15 06:00 PMCR- 2016/09/01 CRDT- 2015/07/02 06:00 PHST- 2014/10/20 00:00 [received] PHST- 2015/06/18 00:00 [accepted] PHST- 2015/07/02 06:00 [entrez] PHST- 2015/07/02 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] PHST- 2016/09/01 00:00 [pmc-release] AID - 0008-5472.CAN-14-2999-T [pii] AID - 10.1158/0008-5472.CAN-14-2999-T [doi] PST - ppublish SO - Cancer Res. 2015 Sep 1;75(17):3623-35. doi: 10.1158/0008-5472.CAN-14-2999-T. Epub 2015 Jun 30.