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Despite the proven effective approach to targeting the phosphatidylinositol-3-kinase (PI3K) pathway in B-cell malignancies, the approved PI3K inhibitors idelalisib and duvelisib have been less commonly selected for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), given the availability of other more tolerable agents. However, patients with CLL/SLL can experience a disease course that is multiply relapsed, refractory, or intolerant to treatment, and PI3K inhibitors can achieve meaningful responses. This article reviews the common early- and late-onset (considered immune-mediated) toxicities with PI3K inhibitors, including infections, hepatotoxicity, diarrhea and/or colitis, and pneumonitis. Data on pretreatment considerations, toxicity management, and drug rechallenge are presented. In addition, next-generation PI3K inhibitors and novel treatment approaches with PI3K inhibitors, including combinations, time-limited treatments, and intermittent dosing, are highlighted., Competing Interests: Conflict-of-interest disclosure: D.M.B. discloses the following: AbbVie: consultant, scientific advisory board, site principal investigator (PI) of a clinical trial (grant paid to institution); ArQule: scientific advisory board, site PI of a clinical trial (grant paid to institution); Ascentage Pharma: site PI of a clinical trial (grant paid to institution); AstraZeneca: consultant, site PI of a clinical trial (grant paid to institution); BeiGene: site PI of a clinical trial (grant paid to institution); DTRM Biopharma: site PI of a clinical trial (grant paid to institution); Genentech: consultant, scientific advisory board, site PI of a clinical trial (grant paid to institution); Juno/Celgene/Bristol-Myers Squibb: site PI of a clinical trial (grant paid to institution); MEI Pharma: site PI of a clinical trial (grant paid to institution); Pharmacyclics: consultant, site PI of a clinical trial (grant paid to institution); Pfizer: consultant, scientific advisory board; Teva: consultant; TG Therapeutics: scientific advisory board, site PI of a clinical trial (grant paid to institution); Tolero Pharmaceuticals: site PI of a clinical trial (grant paid to institution); and Verastem Oncology: consultant, scientific advisory board, site PI of a clinical trial (grant paid to institution). Other guidelines/registry memberships (when sponsored or consultant also included under sponsor above): National Comprehensive Cancer Network panel member, informCLL Registry steering committee (AbbVie), Observational Trial of Real-World Treatment Utilization and Effectiveness of PI3K-inhibitors in CLL/SLL and FL (REAL) registry steering committee (Verastem Oncology), and a biosimilars outcomes research panel (Pfizer). A.H. declares no competing financial interests., (© 2020 by The American Society of Hematology.)

The PI3K/AKT signaling pathway is one of the most frequently activated signaling networks in human cancers and has become a valuable target in anticancer therapy. However, accumulating reports suggest that adverse effects such as severe liver injury and inflammation may accompany treatment with pan-PI3K and pan-AKT inhibitors. Our prior work has demonstrated that activation of the PI3K/AKT pathway has a protective role in Fas- or TNFα-induced hepatocytic cell death and liver injury. We postulated that PI3K or AKT inhibitors may exacerbate liver damage via the death factor-mediated hepatocyte apoptosis. In this study we found that several drugs targeting PI3K/AKT either clinically used or in clinical trials sensitized hepatocytes to agonistic anti-Fas antibody- or TNFα-induced apoptosis and significantly shortened the survival of mice in in vivo liver damage models. The PI3K or AKT inhibitors promoted Fas aggregation, inhibited the expression of cellular FLICE-inhibitory protein S and L (FLIP L/S ), and enhanced procaspase-8 activation. Conversely, cotreatment with the AKT specific activator SC79 reversed these effects. Taken together, these findings suggest that PI3K or AKT inhibitors may render hepatocytes hypersensitive to Fas- or TNFα-induced apoptosis and liver injury., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Previously, we showed that inhibition of the protein kinase C β (PKCβ)/AKT pathway augments engagement of the histone deacetylase inhibitor (HDI)-induced apoptosis in lymphoma cells. In the present study, we investigated the cytotoxicity and mechanisms of cell death induced by the delta isoform-specific phosphatidylinositide 3-kinase (PI3K) inhibitor, GS-1101, in combination with the HDI, panobinostat (LBH589) and suberoylanilide hydroxamic acid (SAHA). Lymphoma cell lines, primary non-Hodgkin Lymphoma (NHL) and chronic lymphocytic leukaemia (CLL) cells were simultaneously treated with the HDI, LBH589 and GS-1101. An interaction of the LBH589/GS-1101 combination was formally examined by using various concentrations of LBH589 and GS-1101. Combined treatment resulted in a synergistic inhibition of proliferation and showed synergistic effect on apoptotic induction in all tested cell lines and primary NHL and CLL cells. This study indicates that interference with PI3K signalling dramatically increases HDI-mediated apoptosis in malignant haematopoietic cells, possibly through both AKT-dependent or AKT- independent mechanisms. Moreover, the increase in HDI-related apoptosis observed in PI3K inhibitor-treated cells appears to be related to the disruption of the extracellular signal-regulated kinase (ERK) signalling pathway. This study provides a strong rational for testing the combination of PI3K inhibitors and HDI in the clinic., (© 2013 John Wiley & Sons Ltd.)