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PI 3 KCA plays a major role in multiple myeloma and its inhibition with BYL 719 decreases proliferation, synergizes with other therapies and overcomes stroma‐induced resistance
Author(s) -
Azab Feda,
Vali Shireen,
Abraham Joseph,
Potter Nicholas,
Muz Barbara,
Puente Pilar,
Fiala Mark,
Paasch Jacob,
Sultana Zeba,
Tyagi Anuj,
Abbasi Taher,
Vij Ravi,
Azab Abdel Kareem
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.12734
Subject(s) - bortezomib , apoptosis , pi3k/akt/mtor pathway , medicine , carfilzomib , cancer research , pharmacology , cell growth , cell cycle , bone marrow , multiple myeloma , immunology , biology , biochemistry , genetics
Summary The phosphatidylinositide 3‐kinase ( PI 3K) pathway is activated and correlated with drug resistance in multiple myeloma ( MM ). In the present study we investigated the role of PI 3 KCA ( PI 3K‐α) in the progression and drug resistance in MM . We showed that the gene expression of PI 3 KCA isoform was higher in MM compared to normal subjects. BYL 719, a novel and specific PI 3 KCA inhibitor inhibited the survival of primary MM cells and cell lines but not normal peripheral blood mononuclear cells. BYL 719 induced the apoptosis of MM cells and inhibited their cell cycle by causing G1 arrest. BYL 719 inhibited PI 3K signalling, decreased proliferation and cells cycle signalling, and induced apoptosis signalling in MM cells. Finally, BYL 719 synergized with bortezomib and carfilzomib, and overcame drug resistance induced by bone marrow stroma. These results were confirmed using in silico simulation of MM cell lines, BYL 719 and bortezomib, and showed similar trends in survival, proliferation, apoptosis, cell signalling and synergy with drugs. In conclusion, PI 3 KCA plays a major role in proliferation and drug resistance of MM cells, the effects of which were inhibited with BYL 719. These results provide a preclinical basis for a future clinical trial of BYL 719 in MM as a single agent or in combination with other drugs.