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Targeting phosphatidylinositol 3 kinase-β and -δ for Bruton tyrosine kinase resistance in diffuse large B-cell lymphoma

N. Jain, S. Singh, G. Laliotis, A. Hart, E. Muhowski, K. Kupcova, T. Chrbolkova, T. Khashab, SM. Chowdhury, A. Sircar, F. Shirazi, RK. Singh, L. Alinari, J. Zhu, O. Havranek, P. Tsichlis, J. Woyach, R. Baiocchi, F. Samaniego, L. Sehgal

. 2020 ; 4 (18) : 4382-4392. [pub] 20200922

Jazyk angličtina Země Spojené státy americké

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21020110

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse after a complete response or are refractory to therapy. To survive, the activated B-cell (ABC) subtype of DLBCL relies upon B-cell receptor signaling, which can be modulated by the activity of Bruton tyrosine kinase (BTK). Targeting BTK with ibrutinib, an inhibitor, provides a therapeutic approach for this subtype of DLBCL. However, non-Hodgkin lymphoma is often resistant to ibrutinib or acquires resistance soon after exposure. We explored how this resistance develops. We generated 3 isogenic ibrutinib-resistant DLBCL cell lines and investigated the deregulated pathways known to be associated with tumorigenic properties. Reduced levels of BTK and enhanced phosphatidylinositol 3-kinase (PI3K)/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of PI3K-β expression was demonstrated to drive resistance in ibrutinib-resistant cells, and resistance was reversed by the blocking activity of PI3K-β/δ. Treatment with the selective PI3K-β/δ dual inhibitor KA2237 reduced both tumorigenic properties and survival-based PI3K/AKT/mTOR signaling of these ibrutinib-resistant cells. In addition, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited metabolic growth. This study elucidates the compensatory upregulated PI3K/AKT axis that emerges in ibrutinib-resistant cells.

Citace poskytuje Crossref.org

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$a Targeting phosphatidylinositol 3 kinase-β and -δ for Bruton tyrosine kinase resistance in diffuse large B-cell lymphoma / $c N. Jain, S. Singh, G. Laliotis, A. Hart, E. Muhowski, K. Kupcova, T. Chrbolkova, T. Khashab, SM. Chowdhury, A. Sircar, F. Shirazi, RK. Singh, L. Alinari, J. Zhu, O. Havranek, P. Tsichlis, J. Woyach, R. Baiocchi, F. Samaniego, L. Sehgal
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