Dual inhibition of VEGF and PARP suppresses KRAS-mutant colorectal cancer
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved..
The addition of bevacizumab to chemotherapy has prolonged overall and progression-free survival rates for metastatic colorectal cancer (mCRC). However, KRAS-mutant (KRAS-mut) CRC, lacking an ideal targeted agent, represents an inferior-response subgroup of patients. In the present study, we investigated a combination approach of bevacizumab + olaparib in KRAS-mut CRC in a preclinical setting. The combined therapy effectively prevented tumor growth in a KRAS-mut cancer cell-derived xenograft model, although this effect was not observed in vitro. Under bevacizumab treatment, we detected intratumor hypoxia and impaired homologous recombination repair (HRR), accompanied by vascular regression. We explored the underlying mechanism of this combined therapy by mimicking a hypoxic condition in vitro using cobalt chloride (CoCl2). The results showed that hypoxia impairs HRR and therefore sensitized KRAS-mut CRC cell lines HCT-116, SW620, and Lovo to olaparib. Furthermore, under this hypoxic condition, olaparib could arrest the cell cycle in the G2/M phase, increase DNA damage and dramatically induce cell apoptosis in KRAS-mut CRC cells. Taken together, these results indicated that the combination of bevacizumab + olaparib could be a potential therapeutic approach in a KRAS-mut CRC cohort.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Neoplasia (New York, N.Y.) - 22(2020), 9 vom: 01. Sept., Seite 365-375 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhong, Longhui [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.07.2021 Date Revised 29.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.neo.2020.06.001 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM312068506 |
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| 100 | 1 | |a Zhong, Longhui |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Dual inhibition of VEGF and PARP suppresses KRAS-mutant colorectal cancer |
| 264 | 1 | |c 2020 | |
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| 500 | |a Date Completed 12.07.2021 | ||
| 500 | |a Date Revised 29.03.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a The addition of bevacizumab to chemotherapy has prolonged overall and progression-free survival rates for metastatic colorectal cancer (mCRC). However, KRAS-mutant (KRAS-mut) CRC, lacking an ideal targeted agent, represents an inferior-response subgroup of patients. In the present study, we investigated a combination approach of bevacizumab + olaparib in KRAS-mut CRC in a preclinical setting. The combined therapy effectively prevented tumor growth in a KRAS-mut cancer cell-derived xenograft model, although this effect was not observed in vitro. Under bevacizumab treatment, we detected intratumor hypoxia and impaired homologous recombination repair (HRR), accompanied by vascular regression. We explored the underlying mechanism of this combined therapy by mimicking a hypoxic condition in vitro using cobalt chloride (CoCl2). The results showed that hypoxia impairs HRR and therefore sensitized KRAS-mut CRC cell lines HCT-116, SW620, and Lovo to olaparib. Furthermore, under this hypoxic condition, olaparib could arrest the cell cycle in the G2/M phase, increase DNA damage and dramatically induce cell apoptosis in KRAS-mut CRC cells. Taken together, these results indicated that the combination of bevacizumab + olaparib could be a potential therapeutic approach in a KRAS-mut CRC cohort | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Bevacizumab | |
| 650 | 4 | |a Colorectal cancer | |
| 650 | 4 | |a Homologous-recombination repair | |
| 650 | 4 | |a KRAS | |
| 650 | 4 | |a Olaparib | |
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| 650 | 7 | |a Phthalazines |2 NLM | |
| 650 | 7 | |a Piperazines |2 NLM | |
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| 700 | 1 | |a Wang, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Yanxia |e verfasserin |4 aut | |
| 700 | 1 | |a Peng, Shunli |e verfasserin |4 aut | |
| 700 | 1 | |a Ma, Yueyun |e verfasserin |4 aut | |
| 700 | 1 | |a Ding, Sijie |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Hong |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Shiyu |e verfasserin |4 aut | |
| 700 | 1 | |a Luo, Xiaoqing |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Wei |e verfasserin |4 aut | |
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