BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress
Abstract BH3 mimetic drugs that inhibit BCL-2, BCL-XL, or MCL-1 have limited activity in solid tumors. Through assessment of xenograft-derived 3D prostate cancer models and cell lines we find that tumors with RB1 loss are sensitive to BCL-XL inhibition. In parallel, drug screening demonstrates that...
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Nature Portfolio
2025-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-60238-x |
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| author | Andreas Varkaris Keshan Wang Mannan Nouri Nina Kozlova Daniel R. Schmidt Anastasia Stavridi Seiji Arai Nicholas Ambrosio Larysa Poluben Juan M. Jimenez-Vacas Daniel Westaby Juliet Carmichael Fang Xie Ines Figueiredo Lorenzo Buroni Antje Neeb Bora Gurel Nicholas Chevalier Lisha Brown Olga Voznesensky Shao-Yong Chen Joshua W. Russo Xin Yuan Dejan Juric Himisha Beltran Johann S. De Bono Matthew G. Vander Heiden David J. Einstein Taru Muranen Eva Corey Adam Sharp Steven P. Balk |
| author_facet | Andreas Varkaris Keshan Wang Mannan Nouri Nina Kozlova Daniel R. Schmidt Anastasia Stavridi Seiji Arai Nicholas Ambrosio Larysa Poluben Juan M. Jimenez-Vacas Daniel Westaby Juliet Carmichael Fang Xie Ines Figueiredo Lorenzo Buroni Antje Neeb Bora Gurel Nicholas Chevalier Lisha Brown Olga Voznesensky Shao-Yong Chen Joshua W. Russo Xin Yuan Dejan Juric Himisha Beltran Johann S. De Bono Matthew G. Vander Heiden David J. Einstein Taru Muranen Eva Corey Adam Sharp Steven P. Balk |
| author_sort | Andreas Varkaris |
| collection | DOAJ |
| description | Abstract BH3 mimetic drugs that inhibit BCL-2, BCL-XL, or MCL-1 have limited activity in solid tumors. Through assessment of xenograft-derived 3D prostate cancer models and cell lines we find that tumors with RB1 loss are sensitive to BCL-XL inhibition. In parallel, drug screening demonstrates that disruption of nucleotide pools by agents including thymidylate synthase inhibitors sensitizes to BCL-XL inhibition, together indicating that replication stress increases dependence on BCL-XL. Mechanistically we establish that replication stress sensitizes to BCL-XL inhibition through TP53/CDKN1A-dependent suppression of BIRC5 expression. Therapy with a BCL-2/BCL-XL inhibitor (navitoclax) in combination with thymidylate synthase inhibitors (raltitrexed or capecitabine) causes marked and prolonged tumor regression in prostate and breast cancer xenograft models. These findings indicate that BCL-XL inhibitors may be effective as single agents in a subset of solid tumors with RB1 loss, and that pharmacological induction of replication stress may be a broadly applicable approach for sensitizing to BCL-XL inhibitors. |
| format | Article |
| id | doaj-art-b409d7dee3f54934896600988205eff5 |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-b409d7dee3f54934896600988205eff52025-08-20T03:16:51ZengNature PortfolioNature Communications2041-17232025-05-0116111710.1038/s41467-025-60238-xBH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stressAndreas Varkaris0Keshan Wang1Mannan Nouri2Nina Kozlova3Daniel R. Schmidt4Anastasia Stavridi5Seiji Arai6Nicholas Ambrosio7Larysa Poluben8Juan M. Jimenez-Vacas9Daniel Westaby10Juliet Carmichael11Fang Xie12Ines Figueiredo13Lorenzo Buroni14Antje Neeb15Bora Gurel16Nicholas Chevalier17Lisha Brown18Olga Voznesensky19Shao-Yong Chen20Joshua W. Russo21Xin Yuan22Dejan Juric23Himisha Beltran24Johann S. De Bono25Matthew G. Vander Heiden26David J. Einstein27Taru Muranen28Eva Corey29Adam Sharp30Steven P. Balk31Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolInstitute of Cancer Research, Royal Marsden NHS Foundation TrustInstitute of Cancer Research, Royal Marsden NHS Foundation TrustInstitute of Cancer Research, Royal Marsden NHS Foundation TrustDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolInstitute of Cancer Research, Royal Marsden NHS Foundation TrustInstitute of Cancer Research, Royal Marsden NHS Foundation TrustInstitute of Cancer Research, Royal Marsden NHS Foundation TrustInstitute of Cancer Research, Royal Marsden NHS Foundation TrustMassachusetts General Cancer Center and Department of Medicine, Harvard Medical SchoolDepartment of Urology, University of WashingtonDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolMassachusetts General Cancer Center and Department of Medicine, Harvard Medical SchoolDana-Farber Cancer InstituteInstitute of Cancer Research, Royal Marsden NHS Foundation TrustKoch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Urology, University of WashingtonInstitute of Cancer Research, Royal Marsden NHS Foundation TrustDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical SchoolAbstract BH3 mimetic drugs that inhibit BCL-2, BCL-XL, or MCL-1 have limited activity in solid tumors. Through assessment of xenograft-derived 3D prostate cancer models and cell lines we find that tumors with RB1 loss are sensitive to BCL-XL inhibition. In parallel, drug screening demonstrates that disruption of nucleotide pools by agents including thymidylate synthase inhibitors sensitizes to BCL-XL inhibition, together indicating that replication stress increases dependence on BCL-XL. Mechanistically we establish that replication stress sensitizes to BCL-XL inhibition through TP53/CDKN1A-dependent suppression of BIRC5 expression. Therapy with a BCL-2/BCL-XL inhibitor (navitoclax) in combination with thymidylate synthase inhibitors (raltitrexed or capecitabine) causes marked and prolonged tumor regression in prostate and breast cancer xenograft models. These findings indicate that BCL-XL inhibitors may be effective as single agents in a subset of solid tumors with RB1 loss, and that pharmacological induction of replication stress may be a broadly applicable approach for sensitizing to BCL-XL inhibitors.https://doi.org/10.1038/s41467-025-60238-x |
| spellingShingle | Andreas Varkaris Keshan Wang Mannan Nouri Nina Kozlova Daniel R. Schmidt Anastasia Stavridi Seiji Arai Nicholas Ambrosio Larysa Poluben Juan M. Jimenez-Vacas Daniel Westaby Juliet Carmichael Fang Xie Ines Figueiredo Lorenzo Buroni Antje Neeb Bora Gurel Nicholas Chevalier Lisha Brown Olga Voznesensky Shao-Yong Chen Joshua W. Russo Xin Yuan Dejan Juric Himisha Beltran Johann S. De Bono Matthew G. Vander Heiden David J. Einstein Taru Muranen Eva Corey Adam Sharp Steven P. Balk BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress Nature Communications |
| title | BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress |
| title_full | BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress |
| title_fullStr | BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress |
| title_full_unstemmed | BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress |
| title_short | BH3 mimetics targeting BCL-XL have efficacy in solid tumors with RB1 loss and replication stress |
| title_sort | bh3 mimetics targeting bcl xl have efficacy in solid tumors with rb1 loss and replication stress |
| url | https://doi.org/10.1038/s41467-025-60238-x |
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