Targeting KRAS‐mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2
The Kirsten rat sarcoma (KRAS) oncogene was considered “undruggable” until the development of sotorasib, a KRASG12C selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRASG12D inhibitor, has shown promising results in basic research, although its effects against...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-02-01
|
| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.13751 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832540631330717696 |
|---|---|
| author | Satoru Miyazaki Masato Kitazawa Satoshi Nakamura Makoto Koyama Yuta Yamamoto Nao Hondo Masahiro Kataoka Hirokazu Tanaka Michiko Takeoka Daisuke Komatsu Yuji Soejima |
| author_facet | Satoru Miyazaki Masato Kitazawa Satoshi Nakamura Makoto Koyama Yuta Yamamoto Nao Hondo Masahiro Kataoka Hirokazu Tanaka Michiko Takeoka Daisuke Komatsu Yuji Soejima |
| author_sort | Satoru Miyazaki |
| collection | DOAJ |
| description | The Kirsten rat sarcoma (KRAS) oncogene was considered “undruggable” until the development of sotorasib, a KRASG12C selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRASG12D inhibitor, has shown promising results in basic research, although its effects against pancreatic cancer are limited when used alone. Therefore, there is an urgent need to identify effective drugs that can be used in combination with KRAS inhibitors. In this study, we found that administration of the KRAS inhibitors sotorasib or MRTX1133 upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. The addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition in vitro and in vivo. Analyses of sotorasib‐ and MRTX1133‐resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2‐mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS‐mutant pancreatic cancer. |
| format | Article |
| id | doaj-art-d14149042f2f4fd7b6ae31dff45e21ef |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-d14149042f2f4fd7b6ae31dff45e21ef2025-02-04T17:30:20ZengWileyMolecular Oncology1574-78911878-02612025-02-0119237739010.1002/1878-0261.13751Targeting KRAS‐mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2Satoru Miyazaki0Masato Kitazawa1Satoshi Nakamura2Makoto Koyama3Yuta Yamamoto4Nao Hondo5Masahiro Kataoka6Hirokazu Tanaka7Michiko Takeoka8Daisuke Komatsu9Yuji Soejima10Division of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanDepartment of Surgery Jinai Hospital Ina JapanDivision of Gastroenterological, Hepato‐Biliary‐Pancreatic, Transplantation and Pediatric Surgery, Department of Surgery Shinshu University School of Medicine Matsumoto JapanThe Kirsten rat sarcoma (KRAS) oncogene was considered “undruggable” until the development of sotorasib, a KRASG12C selective inhibitor that shows favorable effects against lung cancers. MRTX1133, a novel KRASG12D inhibitor, has shown promising results in basic research, although its effects against pancreatic cancer are limited when used alone. Therefore, there is an urgent need to identify effective drugs that can be used in combination with KRAS inhibitors. In this study, we found that administration of the KRAS inhibitors sotorasib or MRTX1133 upregulated STAT3 phosphorylation and reactivated ERK through a feedback reaction. The addition of the MEK inhibitor trametinib and the JAK2 inhibitor fedratinib successfully reversed this effect and resulted in significant growth inhibition in vitro and in vivo. Analyses of sotorasib‐ and MRTX1133‐resistant cells showed that trametinib plus fedratinib reversed the resistance to sotorasib or MRTX1133. These findings suggest that the JAK2‐mediated pathway and reactivation of the MAPK pathway may play key roles in resistance to KRAS inhibitors in pancreatic cancers. Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS‐mutant pancreatic cancer.https://doi.org/10.1002/1878-0261.13751fedratinibKRASMRTX1133pancreatic cancersotorasibtrametinib |
| spellingShingle | Satoru Miyazaki Masato Kitazawa Satoshi Nakamura Makoto Koyama Yuta Yamamoto Nao Hondo Masahiro Kataoka Hirokazu Tanaka Michiko Takeoka Daisuke Komatsu Yuji Soejima Targeting KRAS‐mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2 Molecular Oncology fedratinib KRAS MRTX1133 pancreatic cancer sotorasib trametinib |
| title | Targeting KRAS‐mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2 |
| title_full | Targeting KRAS‐mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2 |
| title_fullStr | Targeting KRAS‐mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2 |
| title_full_unstemmed | Targeting KRAS‐mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2 |
| title_short | Targeting KRAS‐mutant pancreatic cancer through simultaneous inhibition of KRAS, MEK, and JAK2 |
| title_sort | targeting kras mutant pancreatic cancer through simultaneous inhibition of kras mek and jak2 |
| topic | fedratinib KRAS MRTX1133 pancreatic cancer sotorasib trametinib |
| url | https://doi.org/10.1002/1878-0261.13751 |
| work_keys_str_mv | AT satorumiyazaki targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT masatokitazawa targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT satoshinakamura targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT makotokoyama targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT yutayamamoto targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT naohondo targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT masahirokataoka targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT hirokazutanaka targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT michikotakeoka targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT daisukekomatsu targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 AT yujisoejima targetingkrasmutantpancreaticcancerthroughsimultaneousinhibitionofkrasmekandjak2 |