PI3K-β/δ dual inhibitor sensitized ibrutinib-resistant cells to cytotoxic effects of chemotherapeutic agents. (A) Colony formation assays were performed using ibrutinib-resistant DLBCL cells treated with KA2237. (B) OCI-LY10-IbR tumor cells suspended in a 1:1 Matrigel mixture were implanted subcutaneously into nude mice. Intraperitoneal administration of either KA2237 (100 mg/kg) or saline control was initiated every other day after tumors reached ∼300 mm³. Tumor volumes were reported for all mice for 15 days. (C) Western blot analysis for PI3K/AKT/mTOR signaling pathway from tumor lysates treated with KA2237. (D) Drug dose matrix data of respective ibrutinib-resistant cells. The numbers in each matrix indicate the percent of growth inhibition in cells treated with KA2237 plus 1 of 3 chemotherapeutic agents compared with cells treated with vehicle alone. (E) Graphical image representing the PI3K-β/δ–dependent activation of survival PI3K/AKT signaling in acquired ibrutinib resistance DLBCL cells. This activation of survival-PI3K signaling is blocked by the dual PI3K-β/δ selective inhibitor KA2237. Note: font sizes of the molecules in panel E represent their experimentally observed expression levels. Error bars represent standard error. **P < .01; ***P < .001.