Targeting PI3Kδ in Cancer: A Setback or the End?

Zhonglin Hao^1*Susanne Markesbery Arnold¹Jill Kolesar²

• ¹UK Markey Cancer Center, University of Kentucky, Lexington, Kentucky, United States
• ²College of Pharmacy, The University of Iowa, Iowa City, Iowa, United States

PI3Kδ transduces signals from B and T cells in leukocytes and mediates host immune response. Kinase inhibitors exhibit extraordinary efficacy in reducing the B cell mass in indolent B cell lymphomas. However, the efficacy of this drug class could not be confirmed in subsequent phase 3 clinical trials due, at least in part, to the higher incidence and often severe adverse events including death, leading to voluntary withdrawal of all approved PI3Kδ inhibitors for this indication. Meanwhile, PI3Kδ was found to be critical regulators for multiple immune cells, especially the T regulatory cells negatively impacting tumor immunity. Combination use of immune checkpoint inhibitors with PI3Kδ inhibitors presents a potentially not only tolerable but also more effective approach in solid tumor immunotherapy. Intermittent dosing provides the potent suppressive forces imposed on Treg cells in the tumor immune microenvironment retaining its efficacy while reducing adverse effects. Drug development is hindered by an inability to evaluate many possible schedules, and the PI3K story is representative of this problem. A bold approach in drug development deviating from the traditional determination of maximum tolerated dose approach is needed.