Venetoclax after idelalisib: relevant progress for CLL

Abstract

play an important role in increasing the survival and resistance of many oncogenic kinase-driven leukemic cells to targeted kinase inhibition.Although glutaminolysis contributes a significant proportion of the energy requirements for FLT3-ITD 1 cells under FLT3 inhibitory stress, it is not the only metabolic pathway that is functioning. The CRISPR screen by Gallipoli et al reveals that several other genes associated with metabolic pathways demonstrate significant synergistic lethality with quizartinib. These include genes involved in fatty acid synthesis (MECR) and phosphatidylinositol metabolism (PLCH1). Thus, further investigation, similar to that performed here, is warranted in future studies to uncover the role of these other metabolic pathways in providing energy and promoting survival of FLT3-ITD 1 AML cells during FLT3 inhibition.

Activation of Interferon Signaling in Chronic Lymphocytic Leukemia Cells Contributes to Apoptosis Resistance via a JAK-Src/STAT3/Mcl-1 Signaling Pathway

“…The drugs currently prescribed are a combination of fludarabine-cyclophosphamide-rituximab (FCR), signaling inhibitors targeting B cell receptor (BCR)-associated kinases (i.e., Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib) or the antagonist of the B-cell lymphoma-2 (Bcl-2) anti-apoptotic protein (venetoclax) [16]. Venetoclax has been initially approved for relapsed or refractory CLL patients [17], and today may be prescribed in first-line treatment of untreated CLL patients [18,19]. Unfortunately, these therapies are often accompanied by adverse effects or favored mutations associated to drug resistance [20][21][22].…”

Relation of Neutrophil Gelatinase-Associated Lipocalin Overexpression to the Resistance to Apoptosis of Tumor B Cells in Chronic Lymphocytic Leukemia

“…Another alternative strategy involves targeting the B-cell lymphoma-2 (Bcl-2) anti-apoptotic protein, which is overexpressed in B-cell malignancies [6]. Venetoclax (a BH3 mimetic that inhibits the survival function of Bcl-2) has been approved for the treatment of relapsed CLL patients including those bearing a 17p deletion [7]. However, some patients still relapse after treatment with ibrutinib or venetoclax, and others even fail to respond [6].…”