title: Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199).
abstract: Duvelisib, an oral dual inhibitor of PI3K-δ and PI3K-γ, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.
authors.affiliation: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: V M
authors.initials: VM
authors.lastname: Patel
authors.affiliation: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Balakrishnan
authors.affiliation: Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Douglas
authors.affiliation: Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tibbitts
authors.affiliation: Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
authors.forename: E Y
authors.initials: EY
authors.lastname: Xu
authors.affiliation: Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Kutok
authors.affiliation: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ayers
authors.affiliation: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: A
authors.initials: A
authors.lastname: Sarkar
authors.affiliation: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Guerrieri
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: W G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: N
authors.initials: N
authors.lastname: Jain
authors.affiliation: Infinity Pharmaceuticals Inc., Cambridge, MA, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Stern
authors.affiliation: Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: V
authors.initials: V
authors.lastname: Gandhi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology* / Q000627:therapeutic use; D004357:Drug Synergism; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007546:Isoquinolines; D011687:Purines; D013449:Sulfonamides; C586691:duvelisib; C579720:venetoclax