The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma

V. Munugalavadla, S. Mariathasan, D. Slaga, C. Du, L. Berry, G. Del Rosario, Y. Yan, M. Boe, L. Sun, L. S. Friedman, Marta Chesi, Peter Leif Bergsagel, A. Ebens

Research output: Contribution to journalArticle

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Abstract

The phosphatidylinositol 3′-kinase (PI3K) pathway is dysregulated in multiple myeloma (MM); we therefore tested a highly selective class I PI3K inhibitor, GDC-0941, for anti-myeloma activity. Functional and mechanistic studies were first performed in MM cell lines, then extended to primary MM patient samples cultured in vitro. GDC-0941 was then assessed as a single agent and in various combinations in myeloma tumor xenograft models. We show p110 α and β are the predominant PI3K catalytic subunits in MM and that a highly selective class I PI3K inhibitor, GDC-0941, has robust activity as a single agent to induce cell cycle arrest and apoptosis of both MM cell lines and patient myeloma cells. Mechanistic studies revealed an induction of cell cycle arrest at G 0/G 1, with decreased phospho-FoxO1/3a levels, decreased cyclin D1 and c-myc expression, and an increase in the cell cycle inhibitor, p27kip. Induction of apoptosis correlated with increased expression of the pro-apoptotic BH3-only protein BIM, cleaved caspase 3 and cleaved poly (ADP-ribose) polymerase (PARP). In vitro, GDC-0941 synergized with dexamethasone (Dex) and lenalidomide (combination index values of 0.3-0.4 and 0.4-0.8, respectively); in vivo GDC-0941 has anti-myeloma activity and significantly increases the activity of the standard of care agents in several murine xenograft tumor models (additional tumor growth inhibition of 37-53% (Dex) and 22-72% (lenalidomide)). These data provide a clear therapeutic hypothesis for the inhibition of PI3K and provide a rationale for clinical development of GDC-0941 in myeloma.

Original languageEnglish (US)
Pages (from-to)316-325
Number of pages10
JournalOncogene
Volume33
Issue number3
DOIs
StatePublished - Jan 16 2014

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Phosphatidylinositol 3-Kinase
Multiple Myeloma
Class I Phosphatidylinositol 3-Kinases
Cell Cycle Checkpoints
Heterografts
Dexamethasone
Apoptosis
Cell Line
Neoplasms
Poly(ADP-ribose) Polymerases
Cyclin D1
Standard of Care
Caspase 3
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
Catalytic Domain
Cell Cycle
Growth

Keywords

  • FoxO3A
  • GDC-0941
  • multiple myeloma
  • PI3K

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Munugalavadla, V., Mariathasan, S., Slaga, D., Du, C., Berry, L., Del Rosario, G., ... Ebens, A. (2014). The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma. Oncogene, 33(3), 316-325. https://doi.org/10.1038/onc.2012.594

The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma. / Munugalavadla, V.; Mariathasan, S.; Slaga, D.; Du, C.; Berry, L.; Del Rosario, G.; Yan, Y.; Boe, M.; Sun, L.; Friedman, L. S.; Chesi, Marta; Bergsagel, Peter Leif; Ebens, A.

In: Oncogene, Vol. 33, No. 3, 16.01.2014, p. 316-325.

Research output: Contribution to journalArticle

Munugalavadla, V, Mariathasan, S, Slaga, D, Du, C, Berry, L, Del Rosario, G, Yan, Y, Boe, M, Sun, L, Friedman, LS, Chesi, M, Bergsagel, PL & Ebens, A 2014, 'The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma', Oncogene, vol. 33, no. 3, pp. 316-325. https://doi.org/10.1038/onc.2012.594
Munugalavadla V, Mariathasan S, Slaga D, Du C, Berry L, Del Rosario G et al. The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma. Oncogene. 2014 Jan 16;33(3):316-325. https://doi.org/10.1038/onc.2012.594
Munugalavadla, V. ; Mariathasan, S. ; Slaga, D. ; Du, C. ; Berry, L. ; Del Rosario, G. ; Yan, Y. ; Boe, M. ; Sun, L. ; Friedman, L. S. ; Chesi, Marta ; Bergsagel, Peter Leif ; Ebens, A. / The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma. In: Oncogene. 2014 ; Vol. 33, No. 3. pp. 316-325.
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