PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma

Sarah A. Meadows, Francisco Vega, Adam Kashishian, Dave Johnson, Volker Diehl, Langdon L. Miller, Anas Younes, Brian J. Lannutti

Research output: Contribution to journalArticle

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Abstract

GS-1101 (CAL-101) is an oral PI3Kδ- specific inhibitor that has shown preclinical and clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. To investigate the potential role of PI3Kδ in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kδisoform expression and constitutive PI3K pathway activation. Inhibition of PI3Kδ by GS-1101 resulted in the inhibition of Akt phosphorylation. Cocultures with stroma cells induced Akt activation in HL cells, and this effect was blocked by GS-1101. Conversely, production of the stroma-stimulating chemokine, CCL5, by HL cells was reduced by GS-1101. GS-1101 also induced dose-dependent apoptosis of HL cells at 48 hours. Reductions in cell viability and apoptosis were enhanced when combining GS-1101 with the mTOR inhibitor everolimus. Our findings suggest that excessive PI3Kδ activity is characteristic in HL and support clinical evaluation of GS-1101, alone and in combination, as targeted therapy for HL.

Original languageEnglish
Pages (from-to)1897-1900
Number of pages4
JournalBlood
Volume119
Issue number8
DOIs
StatePublished - Feb 23 2012
Externally publishedYes

Fingerprint

Cellular Microenvironment
Hodgkin Disease
Phosphatidylinositol 3-Kinases
Apoptosis
Chemical activation
Cells
Chemokine CCL5
Phosphorylation
idelalisib
B-Cell Chronic Lymphocytic Leukemia
Coculture Techniques
Non-Hodgkin's Lymphoma
Cell Survival
Cell Line

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. / Meadows, Sarah A.; Vega, Francisco; Kashishian, Adam; Johnson, Dave; Diehl, Volker; Miller, Langdon L.; Younes, Anas; Lannutti, Brian J.

In: Blood, Vol. 119, No. 8, 23.02.2012, p. 1897-1900.

Research output: Contribution to journalArticle

Meadows, Sarah A. ; Vega, Francisco ; Kashishian, Adam ; Johnson, Dave ; Diehl, Volker ; Miller, Langdon L. ; Younes, Anas ; Lannutti, Brian J. / PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. In: Blood. 2012 ; Vol. 119, No. 8. pp. 1897-1900.
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abstract = "GS-1101 (CAL-101) is an oral PI3Kδ- specific inhibitor that has shown preclinical and clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. To investigate the potential role of PI3Kδ in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kδisoform expression and constitutive PI3K pathway activation. Inhibition of PI3Kδ by GS-1101 resulted in the inhibition of Akt phosphorylation. Cocultures with stroma cells induced Akt activation in HL cells, and this effect was blocked by GS-1101. Conversely, production of the stroma-stimulating chemokine, CCL5, by HL cells was reduced by GS-1101. GS-1101 also induced dose-dependent apoptosis of HL cells at 48 hours. Reductions in cell viability and apoptosis were enhanced when combining GS-1101 with the mTOR inhibitor everolimus. Our findings suggest that excessive PI3Kδ activity is characteristic in HL and support clinical evaluation of GS-1101, alone and in combination, as targeted therapy for HL.",
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AU - Kashishian, Adam

AU - Johnson, Dave

AU - Diehl, Volker

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AU - Younes, Anas

AU - Lannutti, Brian J.

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AB - GS-1101 (CAL-101) is an oral PI3Kδ- specific inhibitor that has shown preclinical and clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. To investigate the potential role of PI3Kδ in Hodgkin lymphoma (HL), we screened 5 HL cell lines and primary samples from patients with HL for PI3Kδisoform expression and constitutive PI3K pathway activation. Inhibition of PI3Kδ by GS-1101 resulted in the inhibition of Akt phosphorylation. Cocultures with stroma cells induced Akt activation in HL cells, and this effect was blocked by GS-1101. Conversely, production of the stroma-stimulating chemokine, CCL5, by HL cells was reduced by GS-1101. GS-1101 also induced dose-dependent apoptosis of HL cells at 48 hours. Reductions in cell viability and apoptosis were enhanced when combining GS-1101 with the mTOR inhibitor everolimus. Our findings suggest that excessive PI3Kδ activity is characteristic in HL and support clinical evaluation of GS-1101, alone and in combination, as targeted therapy for HL.

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