Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy
©2019 American Association for Cancer Research..
PURPOSE: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy.Experimental Design: Isogenic ARID1A-/- and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A-/- tumors.
RESULTS: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for recruitment of 53BP1 and RIF1, key mediators of non-homologous end-joining (NHEJ) machinery, to DNA lesions. The inability of ARID1A-/- cells to mount NHEJ repair results in a partial cytotoxic response to radiation. Small-molecule compound screens revealed that PARP inhibitors act synergistically with radiation to potentiate cytotoxicity in ARID1A-/- cells. Combination treatment with low-dose radiation and olaparib greatly improved antitumor efficacy, resulting in long-term remission in mice bearing ARID1A-deficient tumors.
CONCLUSIONS: ARID1A-deficient cells acquire high sensitivity to PARP inhibition after exposure to exogenously induced DNA breaks such as ionizing radiation. Our findings suggest a novel biologically informed strategy for treating ARID1A-deficient malignancies.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2019 |
|---|---|
| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:25 |
|---|---|
| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 25(2019), 18 vom: 15. Sept., Seite 5584-5594 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Park, Youngran [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 07.09.2020 Date Revised 07.09.2020 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1158/1078-0432.CCR-18-4222 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM298135027 |
|---|
| LEADER | 01000naa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM298135027 | ||
| 003 | DE-627 | ||
| 005 | 20231225093512.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2019 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1158/1078-0432.CCR-18-4222 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n0993.xml |
| 035 | |a (DE-627)NLM298135027 | ||
| 035 | |a (NLM)31196855 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Park, Youngran |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Loss of ARID1A in Tumor Cells Renders Selective Vulnerability to Combined Ionizing Radiation and PARP Inhibitor Therapy |
| 264 | 1 | |c 2019 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 07.09.2020 | ||
| 500 | |a Date Revised 07.09.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2019 American Association for Cancer Research. | ||
| 520 | |a PURPOSE: Somatic inactivating mutations in ARID1A, a component of the SWI/SNF chromatin remodeling complex, are detected in various types of human malignancies. Loss of ARID1A compromises DNA damage repair. The induced DNA damage burden may increase reliance on PARP-dependent DNA repair of cancer cells to maintain genome integrity and render susceptibility to PARP inhibitor therapy.Experimental Design: Isogenic ARID1A-/- and wild-type cell lines were used for assessing DNA damage response, DNA compactness, and profiling global serine/threonine phosphoproteomic in vivo. A panel of inhibitors targeting DNA repair pathways was screened for a synergistic antitumor effect with irradiation in ARID1A-/- tumors | ||
| 520 | |a RESULTS: ARID1A-deficient endometrial cells exhibit sustained levels in DNA damage response, a result further supported by in vivo phosphoproteomic analysis. Our results show that ARID1A is essential for establishing an open chromatin state upon DNA damage, a process required for recruitment of 53BP1 and RIF1, key mediators of non-homologous end-joining (NHEJ) machinery, to DNA lesions. The inability of ARID1A-/- cells to mount NHEJ repair results in a partial cytotoxic response to radiation. Small-molecule compound screens revealed that PARP inhibitors act synergistically with radiation to potentiate cytotoxicity in ARID1A-/- cells. Combination treatment with low-dose radiation and olaparib greatly improved antitumor efficacy, resulting in long-term remission in mice bearing ARID1A-deficient tumors | ||
| 520 | |a CONCLUSIONS: ARID1A-deficient cells acquire high sensitivity to PARP inhibition after exposure to exogenously induced DNA breaks such as ionizing radiation. Our findings suggest a novel biologically informed strategy for treating ARID1A-deficient malignancies | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a ARID1A protein, human |2 NLM | |
| 650 | 7 | |a Cell Cycle Proteins |2 NLM | |
| 650 | 7 | |a DNA-Binding Proteins |2 NLM | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 700 | 1 | |a Chui, M Herman |e verfasserin |4 aut | |
| 700 | 1 | |a Suryo Rahmanto, Yohan |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Zheng-Cheng |e verfasserin |4 aut | |
| 700 | 1 | |a Shamanna, Raghavendra A |e verfasserin |4 aut | |
| 700 | 1 | |a Bellani, Marina A |e verfasserin |4 aut | |
| 700 | 1 | |a Gaillard, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Ayhan, Ayse |e verfasserin |4 aut | |
| 700 | 1 | |a Viswanathan, Akila |e verfasserin |4 aut | |
| 700 | 1 | |a Seidman, Michael M |e verfasserin |4 aut | |
| 700 | 1 | |a Franco, Sonia |e verfasserin |4 aut | |
| 700 | 1 | |a Leung, Anthony K L |e verfasserin |4 aut | |
| 700 | 1 | |a Bohr, Vilhelm A |e verfasserin |4 aut | |
| 700 | 1 | |a Shih, Ie-Ming |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Tian-Li |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Clinical cancer research : an official journal of the American Association for Cancer Research |d 1995 |g 25(2019), 18 vom: 15. Sept., Seite 5584-5594 |w (DE-627)NLM09444479X |x 1557-3265 |7 nnns |
| 773 | 1 | 8 | |g volume:25 |g year:2019 |g number:18 |g day:15 |g month:09 |g pages:5584-5594 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1158/1078-0432.CCR-18-4222 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 25 |j 2019 |e 18 |b 15 |c 09 |h 5584-5594 | ||