Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations

Fabrizio Galimberti, Alexander M. Busch, Fadzai Chinyengetere, Tian Ma, David Sekula, Vincent A. Memoli, Konstantin H. Dragnev, Fang Liu, Kevin C. Johnson, Yongli Guo, Sarah J. Freemantle, Angeline S. Andrew, Patricia Greninger, David J. Robbins, Jeff Settleman, Cyril Benes, Ethan Dmitrovsky

Research output: Contribution to journalArticle

Abstract

Hedgehog (HH) pathway Smoothened (Smo) inhibitors are active against Gorlin syndrome-associated basal cell carcinoma (BCC) and medulloblastoma where Patched (Ptch) mutations occur. We interrogated 705 epithelial cancer cell lines for growth response to the Smo inhibitor cyclopamine and for expressed HH pathway-regulated species in a linked genetic database. Ptch and Smo mutations that respectively conferred Smo inhibitor response or resistance were undetected. Previous studies revealed HH pathway activation in lung cancers. Therefore, findings were validated using lung cancer cell lines, transgenic and transplantable murine lung cancer models, and human normal-malignant lung tissue arrays in addition to testing other Smo inhibitors. Cyclopamine sensitivity most significantly correlated with high cyclin E (P=0.000009) and low insulin-like growth factor binding protein 6 (IGFBP6) (P=0.000004) levels. Gli family members were associated with response. Cyclopamine resistance occurred with high GILZ (P=0.002) expression. Newer Smo inhibitors exhibited a pattern of sensitivity similar to cyclopamine. Gain of cyclin E or loss of IGFBP6 in lung cancer cells significantly increased Smo inhibitor response. Cyclin E-driven transgenic lung cancers expressed a gene profile implicating HH pathway activation. Cyclopamine treatment significantly reduced proliferation of murine and human lung cancers. Smo inhibition reduced lung cancer formation in a syngeneic mouse model. In human normal-malignant lung tissue arrays cyclin E, IGFBP6, Gli1 and GILZ were each differentially expressed. Together, these findings indicate that Smo inhibitors should be considered in cancers beyond those with activating HH pathway mutations. This includes tumors that express genes indicating basal HH pathway activation.

Original languageEnglish (US)
Pages (from-to)1751-1761
Number of pages11
JournalInternational Journal of Oncology
Volume41
Issue number5
DOIs
StatePublished - Nov 1 2012
Externally publishedYes

Fingerprint

Hedgehogs
Lung Neoplasms
Epithelial Cells
Cyclin E
Insulin-Like Growth Factor Binding Protein 6
Mutation
Neoplasms
Basal Cell Nevus Syndrome
Genetic Databases
Cell Line
Lung
Medulloblastoma
Basal Cell Carcinoma
Inhibition (Psychology)
Genes
cyclopamine
Growth

Keywords

  • Hedgehog
  • Lung cancer
  • Patched
  • Smoothened

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Galimberti, F., Busch, A. M., Chinyengetere, F., Ma, T., Sekula, D., Memoli, V. A., ... Dmitrovsky, E. (2012). Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations. International Journal of Oncology, 41(5), 1751-1761. https://doi.org/10.3892/ijo.2012.1599

Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations. / Galimberti, Fabrizio; Busch, Alexander M.; Chinyengetere, Fadzai; Ma, Tian; Sekula, David; Memoli, Vincent A.; Dragnev, Konstantin H.; Liu, Fang; Johnson, Kevin C.; Guo, Yongli; Freemantle, Sarah J.; Andrew, Angeline S.; Greninger, Patricia; Robbins, David J.; Settleman, Jeff; Benes, Cyril; Dmitrovsky, Ethan.

In: International Journal of Oncology, Vol. 41, No. 5, 01.11.2012, p. 1751-1761.

Research output: Contribution to journalArticle

Galimberti, F, Busch, AM, Chinyengetere, F, Ma, T, Sekula, D, Memoli, VA, Dragnev, KH, Liu, F, Johnson, KC, Guo, Y, Freemantle, SJ, Andrew, AS, Greninger, P, Robbins, DJ, Settleman, J, Benes, C & Dmitrovsky, E 2012, 'Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations', International Journal of Oncology, vol. 41, no. 5, pp. 1751-1761. https://doi.org/10.3892/ijo.2012.1599
Galimberti, Fabrizio ; Busch, Alexander M. ; Chinyengetere, Fadzai ; Ma, Tian ; Sekula, David ; Memoli, Vincent A. ; Dragnev, Konstantin H. ; Liu, Fang ; Johnson, Kevin C. ; Guo, Yongli ; Freemantle, Sarah J. ; Andrew, Angeline S. ; Greninger, Patricia ; Robbins, David J. ; Settleman, Jeff ; Benes, Cyril ; Dmitrovsky, Ethan. / Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations. In: International Journal of Oncology. 2012 ; Vol. 41, No. 5. pp. 1751-1761.
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