Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas

Lan V. Pham, Shengjian Huang, Hui Zhang, Jun Zhang, Taylor Bell, Shouhao Zhou, Elizabeth Pogue, Zhiyong Ding, Laura Lam, Jason Westin, R. Eric Davis, Ken H. Young, L. Jeffrey Medeiros, Richard J. Ford, Krystle Nomie, Leo Zhang, Michael Wang

Research output: Contribution to journalArticle

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Abstract

Purpose: 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). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo 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. Results: 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. Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition.

Original languageEnglish (US)
Pages (from-to)3967-3980
Number of pages14
JournalClinical Cancer Research
Volume24
Issue number16
DOIs
StatePublished - Aug 15 2018

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B-Cell Lymphoma
Mantle-Cell Lymphoma
Therapeutics
Phosphatidylinositol 3-Kinases
Lymphoma, Large B-Cell, Diffuse
Heterografts
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
Proteomics
Cell Survival
Cell Line
Non-Hodgkin's Lymphoma
DNA Damage
Proteins
B-Lymphocytes
Research Design
Biomarkers
Western Blotting
Phosphorylation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Pham, Lan V. ; Huang, Shengjian ; Zhang, Hui ; Zhang, Jun ; Bell, Taylor ; Zhou, Shouhao ; Pogue, Elizabeth ; Ding, Zhiyong ; Lam, Laura ; Westin, Jason ; Davis, R. Eric ; Young, Ken H. ; Medeiros, L. Jeffrey ; Ford, Richard J. ; Nomie, Krystle ; Zhang, Leo ; Wang, Michael. / Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 16. pp. 3967-3980.
@article{7a541f256feb4bcf888f6a27ea1f4c91,
title = "Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas",
abstract = "Purpose: 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). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo 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. Results: 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. Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition.",
author = "Pham, {Lan V.} and Shengjian Huang and Hui Zhang and Jun Zhang and Taylor Bell and Shouhao Zhou and Elizabeth Pogue and Zhiyong Ding and Laura Lam and Jason Westin and Davis, {R. Eric} and Young, {Ken H.} and Medeiros, {L. Jeffrey} and Ford, {Richard J.} and Krystle Nomie and Leo Zhang and Michael Wang",
year = "2018",
month = "8",
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doi = "10.1158/1078-0432.CCR-17-3004",
language = "English (US)",
volume = "24",
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Pham, LV, Huang, S, Zhang, H, Zhang, J, Bell, T, Zhou, S, Pogue, E, Ding, Z, Lam, L, Westin, J, Davis, RE, Young, KH, Medeiros, LJ, Ford, RJ, Nomie, K, Zhang, L & Wang, M 2018, 'Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas', Clinical Cancer Research, vol. 24, no. 16, pp. 3967-3980. https://doi.org/10.1158/1078-0432.CCR-17-3004

Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas. / Pham, Lan V.; Huang, Shengjian; Zhang, Hui; Zhang, Jun; Bell, Taylor; Zhou, Shouhao; Pogue, Elizabeth; Ding, Zhiyong; Lam, Laura; Westin, Jason; Davis, R. Eric; Young, Ken H.; Medeiros, L. Jeffrey; Ford, Richard J.; Nomie, Krystle; Zhang, Leo; Wang, Michael.

In: Clinical Cancer Research, Vol. 24, No. 16, 15.08.2018, p. 3967-3980.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Strategic therapeutic targeting to overcome venetoclax resistance in aggressive B-cell lymphomas

AU - Pham, Lan V.

AU - Huang, Shengjian

AU - Zhang, Hui

AU - Zhang, Jun

AU - Bell, Taylor

AU - Zhou, Shouhao

AU - Pogue, Elizabeth

AU - Ding, Zhiyong

AU - Lam, Laura

AU - Westin, Jason

AU - Davis, R. Eric

AU - Young, Ken H.

AU - Medeiros, L. Jeffrey

AU - Ford, Richard J.

AU - Nomie, Krystle

AU - Zhang, Leo

AU - Wang, Michael

PY - 2018/8/15

Y1 - 2018/8/15

N2 - Purpose: 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). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo 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. Results: 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. Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition.

AB - Purpose: 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). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo 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. Results: 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. Conclusions: 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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U2 - 10.1158/1078-0432.CCR-17-3004

DO - 10.1158/1078-0432.CCR-17-3004

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