A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved..
The tumor-suppressor p53 is commonly inactivated in colorectal cancer and pancreatic ductal adenocarcinoma, but existing treatment options for p53-mutant (p53Mut) cancer are largely ineffective. Here, we report a therapeutic strategy for p53Mut tumors based on abnormalities in the DNA repair response. Investigation of DNA repair upon challenge with thymidine analogs reveals a dysregulation in DNA repair response in p53Mut cells that leads to accumulation of DNA breaks. Thymidine analogs do not interrupt DNA synthesis but induce DNA repair that involves a p53-dependent checkpoint. Inhibitors of poly(ADP-ribose) polymerase (PARPis) markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells, whereas p53 wild-type cells respond with p53-dependent inhibition of the cell cycle. Combinations of trifluorothymidine and PARPi agents demonstrate superior anti-neoplastic activity in p53Mut cancer models. These findings support a two-drug combination strategy to improve outcomes for patients with p53Mut cancer.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
|---|---|
| Enthalten in: |
Cell reports. Medicine - 5(2024), 3 vom: 19. März, Seite 101434 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Alruwaili, Mohammed M [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 03.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1016/j.xcrm.2024.101434 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM36877452X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM36877452X | ||
| 003 | DE-627 | ||
| 005 | 20240403235500.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240229s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.xcrm.2024.101434 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1363.xml |
| 035 | |a (DE-627)NLM36877452X | ||
| 035 | |a (NLM)38387463 | ||
| 035 | |a (PII)S2666-3791(24)00057-0 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Alruwaili, Mohammed M |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A synergistic two-drug therapy specifically targets a DNA repair dysregulation that occurs in p53-deficient colorectal and pancreatic cancers |
| 264 | 1 | |c 2024 | |
| 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 22.03.2024 | ||
| 500 | |a Date Revised 03.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a The tumor-suppressor p53 is commonly inactivated in colorectal cancer and pancreatic ductal adenocarcinoma, but existing treatment options for p53-mutant (p53Mut) cancer are largely ineffective. Here, we report a therapeutic strategy for p53Mut tumors based on abnormalities in the DNA repair response. Investigation of DNA repair upon challenge with thymidine analogs reveals a dysregulation in DNA repair response in p53Mut cells that leads to accumulation of DNA breaks. Thymidine analogs do not interrupt DNA synthesis but induce DNA repair that involves a p53-dependent checkpoint. Inhibitors of poly(ADP-ribose) polymerase (PARPis) markedly enhance DNA double-strand breaks and cell death induced by thymidine analogs in p53Mut cells, whereas p53 wild-type cells respond with p53-dependent inhibition of the cell cycle. Combinations of trifluorothymidine and PARPi agents demonstrate superior anti-neoplastic activity in p53Mut cancer models. These findings support a two-drug combination strategy to improve outcomes for patients with p53Mut cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a 5-fluorodeoxyuridine | |
| 650 | 4 | |a DNA damage | |
| 650 | 4 | |a PARP inhibitor | |
| 650 | 4 | |a TAS102 | |
| 650 | 4 | |a colorectal cancer | |
| 650 | 4 | |a pancreatic cancer | |
| 650 | 4 | |a patient-derived xenograft | |
| 650 | 4 | |a poly(ADP-ribose) polymerase | |
| 650 | 4 | |a trifluorothymidine | |
| 650 | 7 | |a Tumor Suppressor Protein p53 |2 NLM | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerase Inhibitors |2 NLM | |
| 650 | 7 | |a Poly(ADP-ribose) Polymerases |2 NLM | |
| 650 | 7 | |a EC 2.4.2.30 |2 NLM | |
| 650 | 7 | |a DNA |2 NLM | |
| 650 | 7 | |a 9007-49-2 |2 NLM | |
| 650 | 7 | |a Thymidine |2 NLM | |
| 650 | 7 | |a VC2W18DGKR |2 NLM | |
| 700 | 1 | |a Zonneville, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Naranjo, Maricris N |e verfasserin |4 aut | |
| 700 | 1 | |a Serio, Hannah |e verfasserin |4 aut | |
| 700 | 1 | |a Melendy, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Straubinger, Robert M |e verfasserin |4 aut | |
| 700 | 1 | |a Gillard, Bryan |e verfasserin |4 aut | |
| 700 | 1 | |a Foster, Barbara A |e verfasserin |4 aut | |
| 700 | 1 | |a Rajan, Priyanka |e verfasserin |4 aut | |
| 700 | 1 | |a Attwood, Kristopher |e verfasserin |4 aut | |
| 700 | 1 | |a Chatley, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Iyer, Renuka |e verfasserin |4 aut | |
| 700 | 1 | |a Fountzilas, Christos |e verfasserin |4 aut | |
| 700 | 1 | |a Bakin, Andrei V |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Cell reports. Medicine |d 2020 |g 5(2024), 3 vom: 19. März, Seite 101434 |w (DE-627)NLM310587662 |x 2666-3791 |7 nnns |
| 773 | 1 | 8 | |g volume:5 |g year:2024 |g number:3 |g day:19 |g month:03 |g pages:101434 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.xcrm.2024.101434 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 5 |j 2024 |e 3 |b 19 |c 03 |h 101434 | ||