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bioRxiv · 10.1101/523761

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

Jain, N.·Havranek, O.·Singh, R. K.·Khashab, T.·Shirazi, F.·Samaniego, F.·Sehgal, L.
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Abstract

Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse following a complete response or are refractory to therapy. The activated subtype of diffuse large B-cell lymphoma relies upon B-cell receptor signaling for survival; this signaling can be modulated by the activity of Brutons tyrosine kinase. Targeting that kinase with its inhibitor ibrutinib provides a potential therapeutic approach for the activated B-cell subtype of diffuse large B-cell lymphoma. However, non-Hodgkin lymphoma is often resistant to ibrutinib or soon develops resistance after exposure to it. In this study, we explored the development of acquired ibrutinib resistance. After generating three isogenic ibrutinib-resistant diffuse large B-cell lymphoma cell lines, we investigated the deregulated pathways that are associated with colony formation, growth rates, and tumorigenic properties. We found that reduced levels of Brutons tyrosine kinase and enhanced phosphatidylinositol 3-kinase/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of phosphatidylinositol-3-kinase-beta expression in those cells drove resistance and was reversed by the blocking activity of phosphatidylinositol-3-kinase-beta/delta. Treatment with the selective phosphatidylinositol-3-kinase-beta/delta dual inhibitor KA2237 reduced both tumorigenic properties and survival-based phosphatidylinositol-3-kinase/AKT/mTOR signaling of these ibrutinib-resistant cells. Additionally, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited the metabolic growth of these ibrutinib-resistant cells. This study elucidates the compensatory upregulated phosphatidylinositol-3-kinase/AKT axis that emerges in ibrutinib-resistant cells.

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Jain, N., Havranek, O., Singh, R. K., Khashab, T., Shirazi, F., Samaniego, F., Sehgal, L.. 2019-01-28. Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma. https://doi.org/10.1101/523761

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