Oncogenic <i>KRAS</i>-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities
Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the <i>KRAS</i> oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patie...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-10-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/21/5481 |
| _version_ | 1797512707819175936 |
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| author | Sapana Bansod Paarth B. Dodhiawala Kian-Huat Lim |
| author_facet | Sapana Bansod Paarth B. Dodhiawala Kian-Huat Lim |
| author_sort | Sapana Bansod |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the <i>KRAS</i> oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network. |
| first_indexed | 2024-03-10T06:05:31Z |
| format | Article |
| id | doaj.art-5d817c7138c64e199ef506aadd7b6506 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T06:05:31Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5d817c7138c64e199ef506aadd7b65062023-11-22T20:35:53ZengMDPI AGCancers2072-66942021-10-011321548110.3390/cancers13215481Oncogenic <i>KRAS</i>-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic OpportunitiesSapana Bansod0Paarth B. Dodhiawala1Kian-Huat Lim2Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USADivision of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USADivision of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USAPancreatic ductal adenocarcinoma (PDAC) remains highly refractory to treatment. While the <i>KRAS</i> oncogene is present in almost all PDAC cases and accounts for many of the malignant feats of PDAC, targeting KRAS or its canonical, direct effector cascades remains unsuccessful in patients. The recalcitrant nature of PDAC is also heavily influenced by its highly fibro-inflammatory tumor microenvironment (TME), which comprises an acellular extracellular matrix and various types of non-neoplastic cells including fibroblasts, immune cells, and adipocytes, underscoring the critical need to delineate the bidirectional signaling interplay between PDAC cells and the TME in order to develop novel therapeutic strategies. The impact of tumor-cell KRAS signaling on various cell types in the TME has been well covered by several reviews. In this article, we critically reviewed evidence, including work from our group, on how the feedback inflammatory signals from the TME impact and synergize with oncogenic KRAS signaling in PDAC cells, ultimately augmenting their malignant behavior. We discussed past and ongoing clinical trials that target key inflammatory pathways in PDAC and highlight lessons to be learned from outcomes. Lastly, we provided our perspective on the future of developing therapeutic strategies for PDAC through understanding the breadth and complexity of KRAS and the inflammatory signaling network.https://www.mdpi.com/2072-6694/13/21/5481inflammationstromapancreatic cancerIRAK4TPL2TAK1 |
| spellingShingle | Sapana Bansod Paarth B. Dodhiawala Kian-Huat Lim Oncogenic <i>KRAS</i>-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities Cancers inflammation stroma pancreatic cancer IRAK4 TPL2 TAK1 |
| title | Oncogenic <i>KRAS</i>-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities |
| title_full | Oncogenic <i>KRAS</i>-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities |
| title_fullStr | Oncogenic <i>KRAS</i>-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities |
| title_full_unstemmed | Oncogenic <i>KRAS</i>-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities |
| title_short | Oncogenic <i>KRAS</i>-Induced Feedback Inflammatory Signaling in Pancreatic Cancer: An Overview and New Therapeutic Opportunities |
| title_sort | oncogenic i kras i induced feedback inflammatory signaling in pancreatic cancer an overview and new therapeutic opportunities |
| topic | inflammation stroma pancreatic cancer IRAK4 TPL2 TAK1 |
| url | https://www.mdpi.com/2072-6694/13/21/5481 |
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