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Front. Oncol. | doi: 10.3389/fonc.2018.00396

Non-canonical Hedgehog pathway activation impedes anticancer effects of Smoothened antagonists in sporadic embryonal rhabdomyosarcoma

 Natalie Geyer1, 2, Rosalie Ridzewski2,  Julia Bauer2,  Kai Dittmann3, Christian Dullin4,  Albert Rosenberger5, Hans-Ulrich Schildhaus6, Anja Uhmann2,  Simone Fulda7 and  Heidi Hahn2*
  • 1Universitätsmedizin Göttingen, Germany
  • 2Institut für Humangenetik, Universitätsmedizin Göttingen, Germany
  • 3Institut für Zelluläre und Molekulare Immunologie, Universitätsmedizin Göttingen, Germany
  • 4Institut für Diagnostische und Interventionelle Radiologie, Universitätsmedizin Göttingen, Germany
  • 5Institut für Genetische Epidemiologie, Universitätsmedizin Göttingen, Germany
  • 6Institut für Pathologie, Universitätsklinikum Göttingen, Germany
  • 7Institut für experimentelle Tumorforschung in der Pädiatrie, Goethe-Universität Frankfurt, Germany

Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show activity of PI3K signaling. In addition, they show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). Our in vitro and in vivo data demonstrate that Smoothened (SMO) antagonists strongly inhibit HH signaling and efficiently reduce proliferation and growth of ERMS showing canonical HH signaling activity due to germline mutations in Ptch. Beyond that the tumors are also highly responsive towards PI3K inhibition, which does not involve modulation of HH signaling activity. Furthermore specific combinations of SMO antagonists and PI3K inhibitors can enhance anticancer effects of either single drug.
This is different in sporadic ERMS, in which mutations in components of the HH pathway are rare. Thus, cell lines derived from sporadic ERMS are nonresponsive to stimulation by SHH or SAG. Moreover, SMO antagonists are not efficient and apparently exert off-target effects. In contrast, PI3K/AKT/mTOR inhibitors efficiently downregulate HH signaling activity in these cells and potently inhibit cellular proliferation. This indicates that HH signaling is non-canonically activated via the PI3K pathway in sporadic ERMS. Furthermore, these data suggest that a medication of sporadic ERMS with SMO inhibitors either requires pretesting or a screen for PTCH mutations and that PI3K inhibitors are in general a better and more reliable therapeutic option for these tumors.

Keywords: ERMS, hh, Ptch, PI3K, Vismodegib, Sonidegib, HhAntag, pictilisib

Received: 16 Jun 2018; Accepted: 31 Aug 2018.

Edited by:

Anat Erdreich-Epstein, Children's Hospital of Los Angeles, United States

Reviewed by:

Aykut Üren, Georgetown University, United States
Marcin Wysoczynski, University of Louisville, United States  

Copyright: © 2018 Geyer, Ridzewski, Bauer, Dittmann, Dullin, Rosenberger, Schildhaus, Uhmann, Fulda and Hahn. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Heidi Hahn, Institut für Humangenetik, Universitätsmedizin Göttingen, Goettingen, Germany, hhahn@gwdg.de