In Vivo Targeting Replication Protein A for Cancer Therapy
Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers....
Ausführliche Beschreibung
Autor*in: |
Pamela S. VanderVere-Carozza [verfasserIn] Navnath S. Gavande [verfasserIn] Shadia I. Jalal [verfasserIn] Karen E. Pollok [verfasserIn] Elmira Ekinci [verfasserIn] Joshua Heyza [verfasserIn] Steve M. Patrick [verfasserIn] Andi Masters [verfasserIn] John J. Turchi [verfasserIn] Katherine S. Pawelczak [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2022 |
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Schlagwörter: |
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Übergeordnetes Werk: |
In: Frontiers in Oncology - Frontiers Media S.A., 2012, 12(2022) |
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Übergeordnetes Werk: |
volume:12 ; year:2022 |
Links: |
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DOI / URN: |
10.3389/fonc.2022.826655 |
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Katalog-ID: |
DOAJ074638785 |
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10.3389/fonc.2022.826655 doi (DE-627)DOAJ074638785 (DE-599)DOAJ1d4434aabcf24c4eb69ee21c9ff5887f DE-627 ger DE-627 rakwb eng RC254-282 Pamela S. VanderVere-Carozza verfasserin aut In Vivo Targeting Replication Protein A for Cancer Therapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers. DNA repair inhibitors Replication Stress Response Replication Protein A DNA damage response DNA repair and cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Navnath S. Gavande verfasserin aut Navnath S. Gavande verfasserin aut Shadia I. Jalal verfasserin aut Karen E. Pollok verfasserin aut Elmira Ekinci verfasserin aut Joshua Heyza verfasserin aut Steve M. Patrick verfasserin aut Andi Masters verfasserin aut John J. Turchi verfasserin aut John J. Turchi verfasserin aut Katherine S. Pawelczak verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 12(2022) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:12 year:2022 https://doi.org/10.3389/fonc.2022.826655 kostenfrei https://doaj.org/article/1d4434aabcf24c4eb69ee21c9ff5887f kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2022.826655/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2022 |
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10.3389/fonc.2022.826655 doi (DE-627)DOAJ074638785 (DE-599)DOAJ1d4434aabcf24c4eb69ee21c9ff5887f DE-627 ger DE-627 rakwb eng RC254-282 Pamela S. VanderVere-Carozza verfasserin aut In Vivo Targeting Replication Protein A for Cancer Therapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers. DNA repair inhibitors Replication Stress Response Replication Protein A DNA damage response DNA repair and cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Navnath S. Gavande verfasserin aut Navnath S. Gavande verfasserin aut Shadia I. Jalal verfasserin aut Karen E. Pollok verfasserin aut Elmira Ekinci verfasserin aut Joshua Heyza verfasserin aut Steve M. Patrick verfasserin aut Andi Masters verfasserin aut John J. Turchi verfasserin aut John J. Turchi verfasserin aut Katherine S. Pawelczak verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 12(2022) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:12 year:2022 https://doi.org/10.3389/fonc.2022.826655 kostenfrei https://doaj.org/article/1d4434aabcf24c4eb69ee21c9ff5887f kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2022.826655/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2022 |
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10.3389/fonc.2022.826655 doi (DE-627)DOAJ074638785 (DE-599)DOAJ1d4434aabcf24c4eb69ee21c9ff5887f DE-627 ger DE-627 rakwb eng RC254-282 Pamela S. VanderVere-Carozza verfasserin aut In Vivo Targeting Replication Protein A for Cancer Therapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers. DNA repair inhibitors Replication Stress Response Replication Protein A DNA damage response DNA repair and cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Navnath S. Gavande verfasserin aut Navnath S. Gavande verfasserin aut Shadia I. Jalal verfasserin aut Karen E. Pollok verfasserin aut Elmira Ekinci verfasserin aut Joshua Heyza verfasserin aut Steve M. Patrick verfasserin aut Andi Masters verfasserin aut John J. Turchi verfasserin aut John J. Turchi verfasserin aut Katherine S. Pawelczak verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 12(2022) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:12 year:2022 https://doi.org/10.3389/fonc.2022.826655 kostenfrei https://doaj.org/article/1d4434aabcf24c4eb69ee21c9ff5887f kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2022.826655/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2022 |
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10.3389/fonc.2022.826655 doi (DE-627)DOAJ074638785 (DE-599)DOAJ1d4434aabcf24c4eb69ee21c9ff5887f DE-627 ger DE-627 rakwb eng RC254-282 Pamela S. VanderVere-Carozza verfasserin aut In Vivo Targeting Replication Protein A for Cancer Therapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers. DNA repair inhibitors Replication Stress Response Replication Protein A DNA damage response DNA repair and cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Navnath S. Gavande verfasserin aut Navnath S. Gavande verfasserin aut Shadia I. Jalal verfasserin aut Karen E. Pollok verfasserin aut Elmira Ekinci verfasserin aut Joshua Heyza verfasserin aut Steve M. Patrick verfasserin aut Andi Masters verfasserin aut John J. Turchi verfasserin aut John J. Turchi verfasserin aut Katherine S. Pawelczak verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 12(2022) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:12 year:2022 https://doi.org/10.3389/fonc.2022.826655 kostenfrei https://doaj.org/article/1d4434aabcf24c4eb69ee21c9ff5887f kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2022.826655/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2022 |
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10.3389/fonc.2022.826655 doi (DE-627)DOAJ074638785 (DE-599)DOAJ1d4434aabcf24c4eb69ee21c9ff5887f DE-627 ger DE-627 rakwb eng RC254-282 Pamela S. VanderVere-Carozza verfasserin aut In Vivo Targeting Replication Protein A for Cancer Therapy 2022 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers. DNA repair inhibitors Replication Stress Response Replication Protein A DNA damage response DNA repair and cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens Navnath S. Gavande verfasserin aut Navnath S. Gavande verfasserin aut Shadia I. Jalal verfasserin aut Karen E. Pollok verfasserin aut Elmira Ekinci verfasserin aut Joshua Heyza verfasserin aut Steve M. Patrick verfasserin aut Andi Masters verfasserin aut John J. Turchi verfasserin aut John J. Turchi verfasserin aut Katherine S. Pawelczak verfasserin aut In Frontiers in Oncology Frontiers Media S.A., 2012 12(2022) (DE-627)684965518 (DE-600)2649216-7 2234943X nnns volume:12 year:2022 https://doi.org/10.3389/fonc.2022.826655 kostenfrei https://doaj.org/article/1d4434aabcf24c4eb69ee21c9ff5887f kostenfrei https://www.frontiersin.org/articles/10.3389/fonc.2022.826655/full kostenfrei https://doaj.org/toc/2234-943X Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2022 |
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Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers. |
abstractGer |
Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers. |
abstract_unstemmed |
Replication protein A (RPA) plays essential roles in DNA replication, repair, recombination, and the DNA damage response (DDR). Retrospective analysis of lung cancer patient data demonstrates high RPA expression as a negative prognostic biomarker for overall survival in smoking-related lung cancers. Similarly, relative expression of RPA is a predictive marker for response to chemotherapy. These observations are consistent with the increase in RPA expression serving as an adaptive mechanism that allows tolerance of the genotoxic stress resulting from carcinogen exposure. We have developed second-generation RPA inhibitors (RPAis) that block the RPA–DNA interaction and optimized formulation for in vivo analyses. Data demonstrate that unlike first-generation RPAis, second-generation molecules show increased cellular permeability and induce cell death via apoptosis. Second-generation RPAis elicit single-agent in vitro anticancer activity across a broad spectrum of cancers, and the cellular response suggests existence of a threshold before chemical RPA exhaustion induces cell death. Chemical RPA inhibition potentiates the anticancer activity of a series of DDR inhibitors and traditional DNA-damaging cancer therapeutics. Consistent with chemical RPA exhaustion, we demonstrate that the effects of RPAi on replication fork dynamics are similar to other known DDR inhibitors. An optimized formulation of RPAi NERx 329 was developed that resulted in single-agent anticancer activity in two non-small cell lung cancer models. These data demonstrate a unique mechanism of action of RPAis eliciting a state of chemical RPA exhaustion and suggest they will provide an effective therapeutic option for difficult-to-treat lung cancers. |
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Navnath S. Gavande Shadia I. Jalal Karen E. Pollok Elmira Ekinci Joshua Heyza Steve M. Patrick Andi Masters John J. Turchi Katherine S. Pawelczak |
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Navnath S. Gavande Shadia I. Jalal Karen E. Pollok Elmira Ekinci Joshua Heyza Steve M. Patrick Andi Masters John J. Turchi Katherine S. Pawelczak |
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10.3389/fonc.2022.826655 |
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2024-07-03T23:59:46.219Z |
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