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PI 3K‐dependent multiple myeloma cell survival is mediated by the PIK 3 CA isoform
Author(s) -
Hofmann Claudia,
Stühmer Thorsten,
Schmiedl Nadine,
Wetzker Reinhard,
Mottok Anja,
Rosenwald Andreas,
Langer Christian,
Zovko Josip,
Chatterjee Manik,
Einsele Hermann,
Bargou Ralf C.,
Steinbrunn Torsten
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12920
Subject(s) - gene isoform , gene knockdown , multiple myeloma , protein kinase b , pi3k/akt/mtor pathway , cancer research , biology , cell culture , immunology , signal transduction , microbiology and biotechnology , genetics , gene
Summary Constitutive phosphatidylinositide 3‐kinase ( PI 3K) signalling has been implicated in multiple myeloma ( MM ) pathophysiology and is regarded as an actionable target for pharmacological intervention. Isoform‐specific PI 3K inhibition may offer the most focused treatment approach and could result in greater clinical efficacy and reduced side effects. We therefore performed isoform‐specific knockdown of PIK 3 CA , PIK 3 CB , PIK 3 CD , and PIK 3 CG to analyse their individual contributions to MM cell survival and downstream signalling. In addition, we tested the effectivity of the novel PI 3K isoform‐specific inhibitors BYL ‐719 ( PIK 3 CA ), TGX ‐221 ( PIK 3 CB ), CAL ‐101 ( PIK 3 CD ), and CAY 10505 ( PIK 3 CG ). We found the PIK 3 CA isoform to be of paramount importance for constitutive Akt activity in MM cells, and – in contrast to inhibition of other class I isoforms – only the blockade of PIK 3 CA was sufficient to induce cell death in a sizeable subgroup of MM samples. Furthermore, pharmacological PIK 3 CA inhibition in combination treatments of BYL ‐719 and established anti‐myeloma agents resulted in strongly enhanced MM cell death. Our data thus clearly indicate therapeutic potential of PIK 3 CA inhibitors and support their clinical evaluation in multiple myeloma.