B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy

Zhang, Liang; Nomie, Krystle; Zhang, Hui; Bell, Taylor; Pham, Lan V.; Kadri, Sabah; Segal, Jeremy P.; Li, Shaoying; Zhou, Shouhao; Santos, David M. Cordas dos; Richard, Shawana; Sharma, Shruti; Chen, Wendy; Oriabure, Onyekachukwu; Liu, Yang; Huang, Shouying; Guo, Haipeng; Chen, Zhihong; Tao, Wenjing; Li, Carrie; Wang, Jack; Fang, Bingliang; Wang, Jacqueline; Li, Lei; Badillo, Maria; Ahmed, Makhdum; Thirumurthi, Selvi; Huang, Steven Y.; Shao, Yiping; Lam, Laura; Yi, Qing; Wang, Lynn; Wang, Michael

doi:10.1158/1078-0432.ccr-16-2703

Cited by 54 publications

(50 citation statements)

References 31 publications

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“…The MCL patient-derived xenograft (PDX) model was established as described previously. 33 All experimental protocols were approved by the Institutional Animal Care and Use Committee of the MD Anderson Cancer Center and performed in accordance with the Declaration of Helsinki. In essence, 6-to 8-week-old male NSG mice (Jackson Laboratory) were housed and monitored in the animal research facility.…”

Section: Pdx Modelmentioning

confidence: 99%

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

Lee

Zhang

et al. 2018

Blood Advances

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The BTK inhibitor ibrutinib has demonstrated a remarkable therapeutic effect in mantle cell lymphoma (MCL). However, approximately one-third of patients do not respond to the drug initially. To identify the mechanisms underlying primary ibrutinib resistance in MCL, we analyzed the transcriptome changes in ibrutinib-sensitive and ibrutinib-resistant cell lines on ibrutinib treatment. We found that MYC gene signature was suppressed by ibrutinib in sensitive but not resistant cell lines. We demonstrated that MYC gene was structurally abnormal and MYC protein was overexpressed in MCL cells. Further, MYC knockdown with RNA interference inhibited cell growth in ibrutinib-sensitive as well as ibrutinib-resistant cells. We explored the possibility of inhibiting MYC through HSP90 inhibition. The chaperon protein is overexpressed in both cell lines and primary MCL cells from the patients. We demonstrated that MYC is a bona fide client of HSP90 in the context of MCL by both immunoprecipitation and chemical precipitation. Furthermore, inhibition of HSP90 using PU-H71 induced apoptosis and caused cell cycle arrest. PU-H71 also demonstrates strong and relatively specific inhibition of the MYC transcriptional program compared with other oncogenic pathways. In a MCL patient-derived xenograft model, the HSP90 inhibitor retards tumor growth and prolongs survival. Last, we showed that PU-H71 induced apoptosis and downregulated MYC protein in MCL cells derived from patients who were clinically resistant to ibrutinib. In conclusion, MYC activity underlies intrinsic resistance to ibrutinib in MCL. As a client protein of HSP90, MYC can be inhibited via PU-H71 to overcome primary ibrutinib resistance.

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Section: Pdx Modelmentioning

confidence: 99%

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

Lee

Zhang

et al. 2018

Blood Advances

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“…28 A previous study indicated the importance of PI3K signaling in the development of ibrutinib resistance in a patientderived xenograft model but a possible mechanism was not proposed. 29 A recent report of mantle cell lymphoma demonstrated that inhibition of the PI3K-alpha isoform in the tumor microenvironment overcame ibrutinib resistance. 30 Because pan-PI3K inhibitors might induce off-target cellular toxicity, we elected to examine the effects of various pharmacological inhibitors of PI3K with different isoform inhibition profiles.…”

Section: Simultaneous Inhibition Of Pi3k-beta and Delta Isoforms Sensmentioning

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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“…Six-to 8-week-old female NOD SCID IL2Rg null (NSG) mice (The Jackson Laboratory) were used to create the PDX models, and all experimental procedures and protocols were approved by The University of Texas MD Anderson Institute Animal Care Committee. As described previously (25), fresh human fetal bones of 17 to 19 gestational weeks (Advanced Bioscience Resources) were subcutaneously implanted into (PT 2) SCID or NSG mice (SCID-hu or NSG-hu). Approximately 4 to 6 weeks following implantation, one injection of 5 Â 10 6 freshly isolated tumor cells from MCL or DLBCL patient samples were administered directly into the human fetal bone implants within the SCID-hu NSG-hu hosts.…”

Section: In Vivo Venetoclax Treatment In Pdx Modelsmentioning

confidence: 99%

Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas

Pham

Huang

Zhang

et al. 2018

Clinical Cancer Research

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B-cell lymphoma-2 (BCL-2), an antiapoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). MCL and DLBCL cell lines, primary patient samples, and patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition. .

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B-Cell Lymphoma Patient-Derived Xenograft Models Enable Drug Discovery and Are a Platform for Personalized Therapy

Cited by 54 publications

References 31 publications

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

Activation of MYC, a bona fide client of HSP90, contributes to intrinsic ibrutinib resistance in mantle cell lymphoma

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

Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas

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