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

Oncogene volume 33, pages 316–325 (2014)Cite this article

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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 G0/G1, 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.

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Acknowledgements

We thank Genentech chemistry group for providing materials, Andy Polson for critical reading of the manuscript, Jeff Wallin and Kyle Edgar for helpful discussions, the IVCC team for technical support, and the especially the patient donors who helped further these work in hopes of helping others.

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Author notes

  1. V Munugalavadla and S Mariathasan: These authors contributed equally to this paper.

Authors and Affiliations

  1. Department of Cancer Immunotherapy and Hematology, Genentech Inc., South San Francisco, CA, USA

    V Munugalavadla, S Mariathasan, D Slaga, C Du, L Berry, G Del Rosario, L Sun, L S Friedman & A Ebens

  2. Department of Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, USA

    Y Yan & M Boe

  3. Department of Medicine, Comprehensive Cancer Center, Mayo Clinic, Scottsdale, AZ, USA

    M Chesi & P Leif Bergsagel

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  1. V Munugalavadla
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Correspondence to V Munugalavadla.

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Competing interests

VM, SM, DS, CD, LB, GD, YY, MB, LS, LF and AE are employees of Genentech, Inc., MC and PB do not have any conflict of interest.

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Munugalavadla, V., Mariathasan, S., Slaga, D. et al. The PI3K inhibitor GDC-0941 combines with existing clinical regimens for superior activity in multiple myeloma. Oncogene 33, 316–325 (2014). https://doi.org/10.1038/onc.2012.594

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  • DOI: https://doi.org/10.1038/onc.2012.594

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