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CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors
BACKGROUND: High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9769062/ https://www.ncbi.nlm.nih.gov/pubmed/36539830 http://dx.doi.org/10.1186/s13046-022-02570-4 |
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author | Lu, Xue He, Yaowu Johnston, Rebecca L. Nanayakarra, Devathri Sankarasubramanian, Sivanandhini Lopez, J. Alejandro Friedlander, Michael Kalimutho, Murugan Hooper, John D. Raninga, Prahlad V. Khanna, Kum Kum |
author_facet | Lu, Xue He, Yaowu Johnston, Rebecca L. Nanayakarra, Devathri Sankarasubramanian, Sivanandhini Lopez, J. Alejandro Friedlander, Michael Kalimutho, Murugan Hooper, John D. Raninga, Prahlad V. Khanna, Kum Kum |
author_sort | Lu, Xue |
collection | PubMed |
description | BACKGROUND: High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs. EXPERIMENTAL DESIGN: We tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo. RESULTS: We show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts. CONCLUSION: Our findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02570-4. |
format | Online Article Text |
id | pubmed-9769062 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-97690622022-12-22 CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors Lu, Xue He, Yaowu Johnston, Rebecca L. Nanayakarra, Devathri Sankarasubramanian, Sivanandhini Lopez, J. Alejandro Friedlander, Michael Kalimutho, Murugan Hooper, John D. Raninga, Prahlad V. Khanna, Kum Kum J Exp Clin Cancer Res Research BACKGROUND: High-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs. EXPERIMENTAL DESIGN: We tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo. RESULTS: We show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts. CONCLUSION: Our findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-022-02570-4. BioMed Central 2022-12-21 /pmc/articles/PMC9769062/ /pubmed/36539830 http://dx.doi.org/10.1186/s13046-022-02570-4 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Lu, Xue He, Yaowu Johnston, Rebecca L. Nanayakarra, Devathri Sankarasubramanian, Sivanandhini Lopez, J. Alejandro Friedlander, Michael Kalimutho, Murugan Hooper, John D. Raninga, Prahlad V. Khanna, Kum Kum CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors |
title | CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors |
title_full | CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors |
title_fullStr | CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors |
title_full_unstemmed | CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors |
title_short | CBL0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to PARP inhibitors |
title_sort | cbl0137 impairs homologous recombination repair and sensitizes high-grade serous ovarian carcinoma to parp inhibitors |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9769062/ https://www.ncbi.nlm.nih.gov/pubmed/36539830 http://dx.doi.org/10.1186/s13046-022-02570-4 |
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