Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 326 (5952): 572-574

Copyright © 2009 by the American Association for the Advancement of Science

Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma

Robert L. Yauch,1 Gerrit J. P. Dijkgraaf,1 Bruno Alicke,1 Thomas Januario,1 Christina P. Ahn,1 Thomas Holcomb,1 Kanan Pujara,1 Jeremy Stinson,1 Christopher A. Callahan,1 Tracy Tang,1 J. Fernando Bazan,1 Zhengyan Kan,1 Somasekar Seshagiri,1 Christine L. Hann,2 Stephen E. Gould,1 Jennifer A. Low,1 Charles M. Rudin,2 Frederic J. de Sauvage1,*

Abstract: The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449–resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein–coupled receptor can serve as a mechanism of drug resistance in human cancer.

1 Genentech, South San Francisco, CA 94080, USA.
2 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.

* To whom correspondence should be addressed. E-mail: sauvage{at}gene.com


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Hedgehog-GLI Signaling Inhibition Suppresses Tumor Growth in Squamous Lung Cancer.
L. Huang, V. Walter, D. N. Hayes, and M. Onaitis (2014)
Clin. Cancer Res. 20, 1566-1575
   Abstract »    Full Text »    PDF »
Open-Label, Exploratory Phase II Trial of Oral Itraconazole for the Treatment of Basal Cell Carcinoma.
D. J. Kim, J. Kim, K. Spaunhurst, J. Montoya, R. Khodosh, K. Chandra, T. Fu, A. Gilliam, M. Molgo, P. A. Beachy, et al. (2014)
J. Clin. Oncol. 32, 745-751
   Abstract »    Full Text »    PDF »
Discovery and Exploitation of Novel Targets by Approved Drugs.
L. Dirix (2014)
J. Clin. Oncol. 32, 720-721
   Full Text »    PDF »
Molecular Pathways: Response and Resistance to BRAF and MEK Inhibitors in BRAFV600E Tumors.
M. D. Thakur and D. D. Stuart (2014)
Clin. Cancer Res. 20, 1074-1080
   Abstract »    Full Text »    PDF »
The rationale for targeted therapies in medulloblastoma.
T. J. MacDonald, D. Aguilera, and R. C. Castellino (2014)
Neuro Oncology 16, 9-20
   Abstract »    Full Text »    PDF »
Vismodegib: An Inhibitor of the Hedgehog Signaling Pathway in the Treatment of Basal Cell Carcinoma.
A. E. Proctor, L. A. Thompson, and C. L. O'Bryant (2014)
Annals of Pharmacotherapy 48, 99-106
   Abstract »    Full Text »    PDF »
PTEN Loss Mitigates the Response of Medulloblastoma to Hedgehog Pathway Inhibition.
C. Metcalfe, B. Alicke, A. Crow, M. Lamoureux, G. J. P. Dijkgraaf, F. Peale, S. E. Gould, and F. J. de Sauvage (2013)
Cancer Res. 73, 7034-7042
   Abstract »    Full Text »    PDF »
Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children.
J. Triscott, C. Lee, C. Foster, B. Manoranjan, M. R. Pambid, R. Berns, A. Fotovati, C. Venugopal, K. O'Halloran, A. Narendran, et al. (2013)
Cancer Res. 73, 6734-6744
   Abstract »    Full Text »    PDF »
Phase I Study of Vismodegib in Children with Recurrent or Refractory Medulloblastoma: A Pediatric Brain Tumor Consortium Study.
A. Gajjar, C. F. Stewart, D. W. Ellison, S. Kaste, L. E. Kun, R. J. Packer, S. Goldman, M. Chintagumpala, D. Wallace, N. Takebe, et al. (2013)
Clin. Cancer Res. 19, 6305-6312
   Abstract »    Full Text »    PDF »
Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups.
L. A. Genovesi, C. G. Ng, M. J. Davis, M. Remke, M. D. Taylor, D. J. Adams, A. G. Rust, J. M. Ward, K. H. Ban, N. A. Jenkins, et al. (2013)
PNAS 110, E4325-E4334
   Abstract »    Full Text »    PDF »
Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases.
S. L. Markant, L. A. Esparza, J. Sun, K. L. Barton, L. M. McCoig, G. A. Grant, J. R. Crawford, M. L. Levy, P. A. Northcott, D. Shih, et al. (2013)
Cancer Res. 73, 6310-6322
   Abstract »    Full Text »    PDF »
The Unfolded Protein Response Selectively Targets Active Smoothened Mutants.
S. Marada, D. P. Stewart, W. J. Bodeen, Y.-G. Han, and S. K. Ogden (2013)
Mol. Cell. Biol. 33, 2375-2387
   Abstract »    Full Text »    PDF »
Prolonged Inhibition of Glioblastoma Xenograft Initiation and Clonogenic Growth following In Vivo Notch Blockade.
Q. Chu, B. A. Orr, S. Semenkow, E. E. Bar, and C. G. Eberhart (2013)
Clin. Cancer Res. 19, 3224-3233
   Abstract »    Full Text »    PDF »
Hypoxia Triggers Hedgehog-Mediated Tumor-Stromal Interactions in Pancreatic Cancer.
T. R. Spivak-Kroizman, G. Hostetter, R. Posner, M. Aziz, C. Hu, M. J. Demeure, D. Von Hoff, S. R. Hingorani, T. B. Palculict, J. Izzo, et al. (2013)
Cancer Res. 73, 3235-3247
   Abstract »    Full Text »    PDF »
Transcriptional Regulation of Serine/Threonine Protein Kinase (AKT) Genes by Glioma-associated Oncogene Homolog 1.
N. K. Agarwal, C. Qu, K. Kunkulla, Y. Liu, and F. Vega (2013)
J. Biol. Chem. 288, 15390-15401
   Abstract »    Full Text »    PDF »
Genomic Medicine Frontier in Human Solid Tumors: Prospects and Challenges.
R. Dienstmann, J. Rodon, J. Barretina, and J. Tabernero (2013)
J. Clin. Oncol. 31, 1874-1884
   Abstract »    Full Text »    PDF »
Combination of Ponatinib with Hedgehog Antagonist Vismodegib for Therapy-Resistant BCR-ABL1-Positive Leukemia.
S. Katagiri, T. Tauchi, S. Okabe, Y. Minami, S. Kimura, T. Maekawa, T. Naoe, and K. Ohyashiki (2013)
Clin. Cancer Res. 19, 1422-1432
   Abstract »    Full Text »    PDF »
Structure and function of the Smoothened extracellular domain in vertebrate Hedgehog signaling.
S. Nachtergaele, D. M. Whalen, L. K. Mydock, Z. Zhao, T. Malinauskas, K. Krishnan, P. W. Ingham, D. F. Covey, C. Siebold, and R. Rohatgi (2013)
eLife Sci 2, e01340
   Abstract »    Full Text »    PDF »
Hedgehog pathway inhibition and the race against tumor evolution.
S. X. Atwood, A. L. S. Chang, and A. E. Oro (2012)
J. Cell Biol. 199, 193-197
   Abstract »    Full Text »    PDF »
Childhood Medulloblastoma: The Paradigm Shift in Molecular Stratification and Treatment Profile.
Z. Sadighi, T. Vats, and S. Khatua (2012)
J Child Neurol 27, 1302-1307
   Abstract »    Full Text »    PDF »
Molecular Pathways: The Hedgehog Signaling Pathway in Cancer.
R. McMillan and W. Matsui (2012)
Clin. Cancer Res. 18, 4883-4888
   Abstract »    Full Text »    PDF »
Small molecule inhibitors of Smoothened ciliary localization and ciliogenesis.
V. M. Wu, S. C. Chen, M. R. Arkin, and J. F. Reiter (2012)
PNAS 109, 13644-13649
   Abstract »    Full Text »    PDF »
Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics.
X. Huang, A. M. Dubuc, R. Hashizume, J. Berg, Y. He, J. Wang, C. Chiang, M. K. Cooper, P. A. Northcott, M. D. Taylor, et al. (2012)
Genes & Dev. 26, 1780-1796
   Abstract »    Full Text »    PDF »
The Utility of Hedgehog Signaling Pathway Inhibition for Cancer.
S. Sahebjam, L. L. Siu, and A. A. Razak (2012)
Oncologist 17, 1090-1099
   Abstract »    Full Text »    PDF »
Vismodegib.
C. M. Rudin (2012)
Clin. Cancer Res. 18, 3218-3222
   Abstract »    Full Text »    PDF »
Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.
M. J. Lee, B. A. Hatton, E. H. Villavicencio, P. C. Khanna, S. D. Friedman, S. Ditzler, B. Pullar, K. Robison, K. F. White, C. Tunkey, et al. (2012)
PNAS 109, 7859-7864
   Abstract »    Full Text »    PDF »
Off-Target Function of the Sonic Hedgehog Inhibitor Cyclopamine in Mediating Apoptosis via Nitric Oxide-Dependent Neutral Sphingomyelinase 2/Ceramide Induction.
M. Meyers-Needham, J. A. Lewis, S. Gencer, R. D. Sentelle, S. A. Saddoughi, C. J. Clarke, Y. A. Hannun, H. Norell, T. M. da Palma, M. Nishimura, et al. (2012)
Mol. Cancer Ther. 11, 1092-1102
   Abstract »    Full Text »    PDF »
Identification of Small Molecule Proliferating Cell Nuclear Antigen (PCNA) Inhibitor That Disrupts Interactions with PIP-box Proteins and Inhibits DNA Replication.
C. Punchihewa, A. Inoue, A. Hishiki, Y. Fujikawa, M. Connelly, B. Evison, Y. Shao, R. Heath, I. Kuraoka, P. Rodrigues, et al. (2012)
J. Biol. Chem. 287, 14289-14300
   Abstract »    Full Text »    PDF »
Hedgehog-EGFR cooperation response genes determine the oncogenic phenotype of basal cell carcinoma and tumour-initiating pancreatic cancer cells.
M. Eberl, S. Klingler, D. Mangelberger, A. Loipetzberger, H. Damhofer, K. Zoidl, H. Schnidar, H. Hache, H.-C. Bauer, F. Solca, et al. (2012)
EMBO Mol Med. 4, 218-233
   Abstract »    Full Text »    PDF »
Polymeric Nanoparticle-Encapsulated Hedgehog Pathway Inhibitor HPI-1 (NanoHHI) Inhibits Systemic Metastases in an Orthotopic Model of Human Hepatocellular Carcinoma.
Y. Xu, V. Chenna, C. Hu, H.-X. Sun, M. Khan, H. Bai, X.-R. Yang, Q.-F. Zhu, Y.-F. Sun, A. Maitra, et al. (2012)
Clin. Cancer Res. 18, 1291-1302
   Abstract »    Full Text »    PDF »
Hedgehog Signaling Inhibition Blocks Growth of Resistant Tumors through Effects on Tumor Microenvironment.
E. Heller, M. A. Hurchla, J. Xiang, X. Su, S. Chen, J. Schneider, K.-S. Joeng, M. Vidal, L. Goldberg, H. Deng, et al. (2012)
Cancer Res. 72, 897-907
   Abstract »    Full Text »    PDF »
CXCR4 Activation Defines a New Subgroup of Sonic Hedgehog-Driven Medulloblastoma.
R. Sengupta, A. Dubuc, S. Ward, L. Yang, P. Northcott, B. M. Woerner, K. Kroll, J. Luo, M. D. Taylor, R. J. Wechsler-Reya, et al. (2012)
Cancer Res. 72, 122-132
   Abstract »    Full Text »    PDF »
A Polymeric Nanoparticle Encapsulated Small-Molecule Inhibitor of Hedgehog Signaling (NanoHHI) Bypasses Secondary Mutational Resistance to Smoothened Antagonists.
V. Chenna, C. Hu, D. Pramanik, B. T. Aftab, C. Karikari, N. R. Campbell, S.-M. Hong, M. Zhao, M. A. Rudek, S. R. Khan, et al. (2012)
Mol. Cancer Ther. 11, 165-173
   Abstract »    Full Text »    PDF »
Antitumoral Effects of Calcitriol in Basal Cell Carcinomas Involve Inhibition of Hedgehog Signaling and Induction of Vitamin D Receptor Signaling and Differentiation.
A. Uhmann, H. Niemann, B. Lammering, C. Henkel, I. Hess, F. Nitzki, A. Fritsch, N. Prufer, A. Rosenberger, C. Dullin, et al. (2011)
Mol. Cancer Ther. 10, 2179-2188
   Abstract »    Full Text »    PDF »
Hedgehog Signaling: Networking to Nurture a Promalignant Tumor Microenvironment.
L. G. Harris, R. S. Samant, and L. A. Shevde (2011)
Mol. Cancer Res. 9, 1165-1174
   Abstract »    Full Text »    PDF »
Pharmacokinetic Dose-Scheduling Study of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors.
P. M. LoRusso, A. Jimeno, G. Dy, A. Adjei, J. Berlin, L. Leichman, J. A. Low, D. Colburn, I. Chang, S. Cheeti, et al. (2011)
Clin. Cancer Res. 17, 5774-5782
   Abstract »    Full Text »    PDF »
Hedgehog Fights Back: Mechanisms of Acquired Resistance against Smoothened Antagonists.
C. Metcalfe and F. J. de Sauvage (2011)
Cancer Res. 71, 5057-5061
   Abstract »    Full Text »    PDF »
Pharmacokinetic-Pharmacodynamic Analysis of Vismodegib in Preclinical Models of Mutational and Ligand-Dependent Hedgehog Pathway Activation.
H. Wong, B. Alicke, K. A. West, P. Pacheco, H. La, T. Januario, R. L. Yauch, F. J. de Sauvage, and S. E. Gould (2011)
Clin. Cancer Res. 17, 4682-4692
   Abstract »    Full Text »    PDF »
Targeting the Hedgehog Pathway in Cancer: Can the Spines Be Smoothened?.
L. Ailles and L. L. Siu (2011)
Clin. Cancer Res. 17, 2071-2073
   Abstract »    Full Text »    PDF »
Phase I Trial of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Refractory, Locally Advanced or Metastatic Solid Tumors.
P. M. LoRusso, C. M. Rudin, J. C. Reddy, R. Tibes, G. J. Weiss, M. J. Borad, C. L. Hann, J. R. Brahmer, I. Chang, W. C. Darbonne, et al. (2011)
Clin. Cancer Res. 17, 2502-2511
   Abstract »    Full Text »    PDF »
Pharmacokinetics of Hedgehog Pathway Inhibitor Vismodegib (GDC-0449) in Patients with Locally Advanced or Metastatic Solid Tumors: the Role of Alpha-1-Acid Glycoprotein Binding.
R. A. Graham, B. L. Lum, S. Cheeti, J. Y. Jin, K. Jorga, D. D. Von Hoff, C. M. Rudin, J. C. Reddy, J. A. Low, and P. M. LoRusso (2011)
Clin. Cancer Res. 17, 2512-2520
   Abstract »    Full Text »    PDF »
PTHrP Treatment Fails to Rescue Bone Defects Caused by Hedgehog Pathway Inhibition in Young Mice.
J. L. Brechbiel, J. M. Y. Ng, and T. Curran (2011)
Toxicol Pathol 39, 478-485
   Abstract »    Full Text »    PDF »
Hedgehog signaling and therapeutics in pancreatic cancer.
F. C. Kelleher (2011)
Carcinogenesis 32, 445-451
   Abstract »    Full Text »    PDF »
Identification and Mechanism of Action of the Acylguanidine MRT-83, a Novel Potent Smoothened Antagonist.
H. Roudaut, E. Traiffort, T. Gorojankina, L. Vincent, H. Faure, A. Schoenfelder, A. Mann, F. Manetti, A. Solinas, M. Taddei, et al. (2011)
Mol. Pharmacol. 79, 453-460
   Abstract »    Full Text »    PDF »
Small Molecule Inhibition of GDC-0449 Refractory Smoothened Mutants and Downstream Mechanisms of Drug Resistance.
G. J. P. Dijkgraaf, B. Alicke, L. Weinmann, T. Januario, K. West, Z. Modrusan, D. Burdick, R. Goldsmith, K. Robarge, D. Sutherlin, et al. (2011)
Cancer Res. 71, 435-444
   Abstract »    Full Text »    PDF »
Clinical Experience With Hedgehog Pathway Inhibitors.
J. A. Low and F. J. de Sauvage (2010)
J. Clin. Oncol. 28, 5321-5326
   Abstract »    Full Text »    PDF »
The Notch Target Hes1 Directly Modulates Gli1 Expression and Hedgehog Signaling: A Potential Mechanism of Therapeutic Resistance.
K. C. Schreck, P. Taylor, L. Marchionni, V. Gopalakrishnan, E. E. Bar, N. Gaiano, and C. G. Eberhart (2010)
Clin. Cancer Res. 16, 6060-6070
   Abstract »    Full Text »    PDF »
Combination Therapy Targeting Both Tumor-Initiating and Differentiated Cell Populations in Prostate Carcinoma.
A. Dubrovska, J. Elliott, R. J. Salamone, S. Kim, L. J. Aimone, J. R. Walker, J. Watson, M. Sauveur-Michel, C. Garcia-Echeverria, C. Y. Cho, et al. (2010)
Clin. Cancer Res. 16, 5692-5702
   Abstract »    Full Text »    PDF »
Virtual Screening-Based Discovery and Mechanistic Characterization of the Acylthiourea MRT-10 Family as Smoothened Antagonists.
F. Manetti, H. Faure, H. Roudaut, T. Gorojankina, E. Traiffort, A. Schoenfelder, A. Mann, A. Solinas, M. Taddei, and M. Ruat (2010)
Mol. Pharmacol. 78, 658-665
   Abstract »    Full Text »    PDF »
Skin Deep and Deeper: Multiple Pathways in Basal Cell Carcinogenesis.
C. D. Peacock and C. M. Rudin (2010)
Cancer Prevention Research 3, 1213-1216
   Abstract »    Full Text »    PDF »
Interfering with Resistance to Smoothened Antagonists by Inhibition of the PI3K Pathway in Medulloblastoma.
S. Buonamici, J. Williams, M. Morrissey, A. Wang, R. Guo, A. Vattay, K. Hsiao, J. Yuan, J. Green, B. Ospina, et al. (2010)
Science Translational Medicine 2, 51ra70
   Abstract »    Full Text »    PDF »
Application of second-generation sequencing to cancer genomics.
K. Robison (2010)
Brief Bioinform 11, 524-534
   Abstract »    Full Text »    PDF »
Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies.
M. Mimeault and S. K. Batra (2010)
Pharmacol. Rev. 62, 497-524
   Abstract »    Full Text »    PDF »
Molecular Therapy Targeting Sonic Hedgehog and Hepatocyte Growth Factor Signaling in a Mouse Model of Medulloblastoma.
V. Coon, T. Laukert, C. A. Pedone, J. Laterra, K. J. Kim, and D. W. Fults (2010)
Mol. Cancer Ther. 9, 2627-2636
   Abstract »    Full Text »    PDF »
Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector.
J. Kim, J. J. Lee, J. Kim, D. Gardner, and P. A. Beachy (2010)
PNAS 107, 13432-13437
   Abstract »    Full Text »    PDF »
Interplay of Dissolution, Solubility, and Nonsink Permeation Determines the Oral Absorption of the Hedgehog Pathway Inhibitor GDC-0449 in Dogs: An Investigation Using Preclinical Studies and Physiologically Based Pharmacokinetic Modeling.
H. Wong, F.-P. Theil, Y. Cui, J. C. Marsters Jr., S. C. Khojasteh, L. Vernillet, H. La, X. Song, H. Wang, E. J. Morinello, et al. (2010)
Drug Metab. Dispos. 38, 1029-1038
   Abstract »    Full Text »    PDF »
The Role of the Hedgehog Signaling Pathway in the Development of Basal Cell Carcinoma and Opportunities for Treatment.
I. Caro and J. A. Low (2010)
Clin. Cancer Res. 16, 3335-3339
   Abstract »    Full Text »    PDF »
Targeting Hedgehog -- a Cancer Stem Cell Pathway.
A. A. Merchant and W. Matsui (2010)
Clin. Cancer Res. 16, 3130-3140
   Abstract »    Full Text »    PDF »
Beyond the Scalpel: Targeting Hedgehog in Skin Cancer Prevention.
C. M. Rudin (2010)
Cancer Prevention Research 3, 1-3
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882