Combination of Ibrutinib and ABT-199 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Kuo, Hsu-Ping; Ezell, Scott A.; Schweighofer, Karl J.; Cheung, Leo W.K.; Hsieh, Sidney; Apatira, Mutiah; Sirisawad, Mint; Eckert, Karl; Hsu, Sara; Chen, Chun‐Te; Beaupre, Darrin M.; Versele, Matthias; Chang, Betty

doi:10.1158/1535-7163.mct-16-0555

Cited by 50 publications

(30 citation statements)

References 34 publications

(32 reference statements)

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“…This is consistent with a previous report that identified elevated BCL2 expression following development of ibrutinib resistance. 35 While venetoclax, an FDA-approved BCL2 inhibitor, can promote anti-proliferative activity for IR-DLBCL, targeting BCL2 could lead to the development of resistance to a BCL2-inhibitor. As an example, one study showed that either short-or long-term exposure of B-cell lymphoma cell lines (MCL and DLBCL) to venetoclax led to the development of venetoclax resistance due to a reduction in PTEN expression (a negative regulator of the PI3K/AKT activation pathway).…”

Section: Discussionmentioning

confidence: 99%

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

Jain

Havránek

Singh

et al. 2019

Preprint

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NJ and LS contributed equally to this work.Abstract: Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma; 40% of patients relapse following a complete response or are refractory to therapy. The activated subtype of diffuse large B-cell lymphoma relies upon B-cell receptor signaling for survival; this signaling can be modulated by the activity of Bruton's tyrosine kinase. Targeting that kinase with its inhibitor ibrutinib provides a potential therapeutic approach for the activated B-cell subtype of diffuse large B-cell lymphoma. However, non-Hodgkin lymphoma is often resistant to ibrutinib or soon develops resistance after exposure to it. In this study, we explored the development of acquired ibrutinib resistance. After generating three isogenic ibrutinib-resistant diffuse large B-cell lymphoma cell lines, we investigated the deregulated pathways that are associated with colony formation, growth rates, and tumorigenic properties. We found that reduced levels of Bruton's tyrosine kinase and enhanced phosphatidylinositol 3-kinase/AKT signaling were hallmarks of these ibrutinib-resistant cells. Upregulation of phosphatidylinositol-3-kinase-beta expression in those cells drove resistance and wasreversed by the blocking activity of phosphatidylinositol-3-kinase-beta/delta. Treatment with the selective phosphatidylinositol-3-kinase-beta/delta dual inhibitor KA2237 reduced both tumorigenic properties and survival-based phosphatidylinositol-3-kinase/AKT/mTOR signaling of these ibrutinibresistant cells. Additionally, combining KA2237 with currently available chemotherapeutic agents synergistically inhibited the metabolic growth of these ibrutinib-resistant cells. This study elucidates the compensatory upregulated phosphatidylinositol-3-kinase/AKT axis that emerges in ibrutinib-resistant cells.

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Section: Discussionmentioning

confidence: 99%

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

Jain

Havránek

Singh

et al. 2019

Preprint

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“…This data aligns with other studies showing that genetic aberrations contribute to ibrutinib resistance in hematological malignancies 47 – 50 . A recent study by Kuo et al showed that ibrutinib resistance is marked by BCL2 upregulation and that combining ibrutinib with ABT-199, a BCL2 inhibitor, could overcome resistance in DLBCL 51 . Together, these studies suggest that genetic analysis of tumors may inform therapeutic choices and highlights the potential importance of individualized therapy based on genetic profiles.…”

Section: Discussionmentioning

confidence: 99%

Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma

Wenzl

Manske

Sarangi

et al. 2018

Blood Cancer Journal

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MYD88 mutations are one of the most recurrent mutations in hematologic malignancies. However, recent mouse models suggest that MYD88L265P alone may not be sufficient to induce tumor formation. Interplay between MYD88L265P and other genetic events is further supported by the fact that TNFAIP3 (A20) inactivation often accompanies MYD88L265P. However, we are still lacking information about the consequence of MYD88L265P in combination with TNFAIP3 loss in human B cell lymphoma. Review of our genetic data on diffuse large B cell lymphoma (DLBCL) and Waldenstrom macroglobulinemia (WM), found that a large percentage of DLBCL and WM cases that have a MYD88 mutation also harbor a TNFAIP3 loss, 55% DLBCL and 28% of WM, respectively. To mimic this combination of genetic events, we used genomic editing technology to knock out TNFAIP3 in MYD88L265P non-Hodgkin’s lymphoma (NHL) cell lines. Loss of A20 expression resulted in increased NF-κB and p38 activity leading to upregulation of the NF-κB target genes BCL2 and MYC. Furthermore, we detected the increased production of IL-6 and CXCL10 which led to an upregulation of the JAK/STAT pathway. Overall, these results suggest that MYD88L265P signaling can be enhanced by a second genetic alteration in TNFAIP3 and highlights a potential opportunity for therapeutic targeting.

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“…Data preprocessing and screening of DEGs. The GSe93984 profile (https://www.ncbi.nlm.nih.gov/pubmed/28428442) and its corresponding platform annotation files were downloaded from the Gene expression omnibus (Geo) database (https://www.ncbi.nlm.nih.gov/geo/) (31). This dataset consisted of 34 samples.…”

Section: Methodsmentioning

confidence: 99%

PDGFD induces ibrutinib resistance of diffuse large B‑cell lymphoma through activation of EGFR

et al. 2020

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ibrutinib, an Fda approved, orally administered BTK inhibitor, has demonstrated high response rates to diffuse large B-cell lymphoma (dlBcl), however, complete responses are infrequent and acquired resistance to BTK inhibition can emerge. The present study investigated the role of the platelet-derived growth factor d (PdGFd) gene and the ibrutinib resistance of dlBcl in relation to epidermal growth factor receptor (eGFr). Bioinformatics was used to screen and analyze differentially expressed genes (deGs) in complete response (cr), partial response (Pr) and stable disease (Sd) in dlBcl treatment with ibrutinib, and Gene ontology (Go) and Kyoto encyclopedia of Genes and Genomes (KeGG) analyses were performed to analyze enriched the signaling pathways increasing deGs. The Search Tool for interactions of chemicals database was used to analyze the target genes of ibrutinib. an interaction network of deGs, disease-related genes and ibrutinib was constructed. The expression of PdGFd in tissues that were resistant or susceptible to dlBcl/ibrutinib was detected via immunohistochemistry (iHc), and the expression of PdGFd in dlBcl/ibrutinib-resistant strains and their parental counterparts were examined via reverse transcription-quantitative Pcr and western blot analyses. Subsequently, a drug-resistant cell model of dlBcl/ibrutinib in which PdGFd was silenced was constructed. The apoptosis of the dlBcl/ibrutinib-resistant strains was examined using MTT and flow cytometry assays. eGFr gene expression was then assessed. at the same time, a PdGFd-interfering plasmid and an eGFr overexpression plasmid were transfected into the dlBcl drug-resistant cells (TMd8-ibrutinib, HBl1-ibrutinib) separately or together. MTT was used to measure cell proliferation and changes in the ic 50 of ibrutinib. a total of 86 deGs that increased in the cr, Pr and Sd tissues were screened, and then evaluated with Go and KeGG. The interaction network diagram showed that there was a regulatory relationship between PdGFd and disease-related genes, and that PdGFd could indirectly target the ibrutinib target gene eGFr, indicating that PdGFd could regulate dlBcl via eGFr. iHc results showed high expression of PdGFd in diffuse large B-cell lymphoma tissues with ibrutinib tolerance. PdGFd expression in ibrutinib-resistant dlBcl cells was higher compared with in parental cells. Following interference with PdGFd expression in ibrutinib-resistant dlBcl cells, the ic 50 value of ibrutinib decreased, the rate of apoptosis increased and eGFr expression decreased. in brief, eGFr overexpression can reverse the resistance of dlBcl to ibrutinib via PDGFD interference, and PdGFd induces the resistance of dlBcl to ibrutinib via eGFr.

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Combination of Ibrutinib and ABT-199 in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Cited by 50 publications

References 34 publications

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

Overcoming ibrutinib resistance by targeting phosphatidylinositol-3-kinase signaling in diffuse large B-cell lymphoma

Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma

PDGFD induces ibrutinib resistance of diffuse large B‑cell lymphoma through activation of EGFR

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