Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling....
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2018-09-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fonc.2018.00396/full |
| _version_ | 1819016576976814080 |
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| author | Natalie Geyer Rosalie Ridzewski Julia Bauer Maria Kuzyakova Kai Dittmann Christian Dullin Albert Rosenberger Hans-Ulrich Schildhaus Anja Uhmann Simone Fulda Heidi Hahn |
| author_facet | Natalie Geyer Rosalie Ridzewski Julia Bauer Maria Kuzyakova Kai Dittmann Christian Dullin Albert Rosenberger Hans-Ulrich Schildhaus Anja Uhmann Simone Fulda Heidi Hahn |
| author_sort | Natalie Geyer |
| collection | DOAJ |
| description | Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations. |
| first_indexed | 2024-12-21T02:49:50Z |
| format | Article |
| id | doaj.art-0b4b41a0b14241158a193fc533725a79 |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-21T02:49:50Z |
| publishDate | 2018-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-0b4b41a0b14241158a193fc533725a792022-12-21T19:18:27ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2018-09-01810.3389/fonc.2018.00396408563Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K InhibitorsNatalie Geyer0Rosalie Ridzewski1Julia Bauer2Maria Kuzyakova3Kai Dittmann4Christian Dullin5Albert Rosenberger6Hans-Ulrich Schildhaus7Anja Uhmann8Simone Fulda9Heidi Hahn10Institute for Human Genetics, University Medical Center Goettingen, Goettingen, GermanyInstitute for Human Genetics, University Medical Center Goettingen, Goettingen, GermanyInstitute for Human Genetics, University Medical Center Goettingen, Goettingen, GermanyInstitute for Human Genetics, University Medical Center Goettingen, Goettingen, GermanyInstitute for Celluar and Molecular Immunology, University Medical Center Goettingen, Goettingen, GermanyInstitute for Diagnostic and Interventional Radiology, University Medical Center Goettingen, Goettingen, GermanyDepartment of Genetic Epidemiology, University Medical Center Goettingen, Goettingen, GermanyInstitute for Pathology, University Medical Center Goettingen, Goettingen, GermanyInstitute for Human Genetics, University Medical Center Goettingen, Goettingen, GermanyInstitute for Experimental Cancer Research in Pediatrics, Goethe-University Frankfurt, Frankfurt, GermanyInstitute for Human Genetics, University Medical Center Goettingen, Goettingen, GermanyRhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. RMS frequently show Hedgehog (HH) pathway activity, which is predominantly seen in the embryonal subtype (ERMS). They also show activation of Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) signaling. Here we compared the therapeutic effectiveness and the impact on HH target gene expression of Smoothened (SMO) antagonists with those of the PI3K inhibitor pictilisib in ERMS with and without mutations in the HH receptor Patched1 (PTCH). Our data demonstrate that growth of ERMS showing canonical Hh signaling activity due to Ptch germline mutations is efficiently reduced by SMO antagonists. This goes along with strong downregulation of the Hh target Gli1. Likewise Ptch mutant tumors are highly responsive toward the PI3K inhibitor pictilisib, which involves modulation of AKT and caspase activity. Pictilisib also modulates Hh target gene expression, which, however, is rather not correlated with its antitumoral effects. In contrast, sporadic ERMS, which usually express HH target genes without having PTCH mutation, apparently lack canonical HH signaling activity. Thus, stimulation by Sonic HE (SHH) or SAG (Smoothened agonist) or inhibition by SMO antagonists do not modulate HH target gene expression. In addition, SMO antagonists do not provoke efficient anticancer effects and rather exert off-target effects. In contrast, pictilisib and other PI3K/AKT/mTOR inhibitors potently inhibit cellular growth. They also efficiently inhibit HH target gene expression. However, of whether this is correlated with their antitumoral effects it is not clear. Together, these data suggest that PI3K inhibitors are a good and reliable therapeutic option for all ERMS, whereas SMO inhibitors might only be beneficial for ERMS driven by PTCH mutations.https://www.frontiersin.org/article/10.3389/fonc.2018.00396/fullERMSHHPTCHPI3Kvismodegibsonidegib |
| spellingShingle | Natalie Geyer Rosalie Ridzewski Julia Bauer Maria Kuzyakova Kai Dittmann Christian Dullin Albert Rosenberger Hans-Ulrich Schildhaus Anja Uhmann Simone Fulda Heidi Hahn Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors Frontiers in Oncology ERMS HH PTCH PI3K vismodegib sonidegib |
| title | Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors |
| title_full | Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors |
| title_fullStr | Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors |
| title_full_unstemmed | Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors |
| title_short | Different Response of Ptch Mutant and Ptch Wildtype Rhabdomyosarcoma Toward SMO and PI3K Inhibitors |
| title_sort | different response of ptch mutant and ptch wildtype rhabdomyosarcoma toward smo and pi3k inhibitors |
| topic | ERMS HH PTCH PI3K vismodegib sonidegib |
| url | https://www.frontiersin.org/article/10.3389/fonc.2018.00396/full |
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