Preclinical Evaluation of a Novel Dual Targeting PI3Kδ/BRD4 Inhibitor, SF2535, in B-Cell Acute Lymphoblastic Leukemia

• Published in: Frontiers in oncology Vol. 11; p. 766888
• Main Authors: Ruan, Yongsheng, Kim, Hye Na, Ogana, Heather A, Wan, Zesheng, Hurwitz, Samantha, Nichols, Cydney, Abdel-Azim, Nour, Coba, Ariana, Seo, Seyoung, Loh, Yong-Hwee Eddie, Gang, Eun Ji, Abdel-Azim, Hisham, Hsieh, Chih-Lin, Lieber, Michael R, Parekh, Chintan, Pal, Dhananjaya, Bhojwani, Deepa, Durden, Donald L, Kim, Yong-Mi
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 01.12.2021
• Subjects: acute lymphoblastic leukemia; BRD4; c-Myc; Oncology; p-AKT; PI3Kδ; SF2535; p-AKT; PI3Kδ; SF2535; acute lymphoblastic leukemia; c-Myc; BRD4
• DOI: 10.3389/fonc.2021.766888
• ISSN: 2234-943X

The PI3K/Akt pathway-and in particular PI3Kδ-is known for its role in drug resistant B-cell acute lymphoblastic leukemia (B-ALL) and it is often upregulated in refractory or relapsed B-ALL. Myc proteins are transcription factors responsible for transcribing pro-proliferative genes and c-Myc is often overexpressed in cancers. The chromatin regulator BRD4 is required for expression of c-Myc in hematologic malignancies including B-ALL. Previously, combination of BRD4 and PI3K inhibition with SF2523 was shown to successfully decrease Myc expression. However, the underlying mechanism and effect of dual inhibition of PI3Kδ/BRD4 in B-ALL remains unknown. To study this, we utilized SF2535, a novel small molecule dual inhibitor which can specifically target the PI3Kδ isoform and BRD4. We treated primary B-ALL cells with various concentrations of SF2535 and studied its effect on specific pharmacological on-target mechanisms such as apoptosis, cell cycle, cell proliferation, and adhesion molecules expression using and models. SF2535 significantly downregulates both c-Myc mRNA and protein expression through inhibition of BRD4 at the c-Myc promoter site and decreases p-AKT expression through inhibition of the PI3Kδ/AKT pathway. SF2535 induced apoptosis in B-ALL by downregulation of BCL-2 and increased cleavage of caspase-3, caspase-7, and PARP. Moreover, SF2535 induced cell cycle arrest and decreased cell counts in B-ALL. Interestingly, SF2535 decreased the mean fluorescence intensity (MFI) of integrin α4, α5, α6, and β1 while increasing MFI of CXCR4, indicating that SF2535 may work through inside-out signaling of integrins. Taken together, our data provide a rationale for the clinical evaluation of targeting PI3Kδ/BRD4 in refractory or relapsed B-ALL using SF2535.