KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening
Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatmen...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2025-02-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13725 |
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| author | Constanza Tapia Contreras Jonas Dominik Falke Dana‐Magdalena Seifert Carolin Schneider Lukas Krauß Xin Fang Denise Müller Engin Demirdizen Melanie Spitzner Tiago De Oliveira Christian Schneeweis Jochen Gaedcke Silke Kaulfuß Kimia Mirzakhani Bernd Wollnik Karly Conrads Tim Beißbarth Gabriela Salinas Jonas Hügel Nils Beyer Sophia Rheinländer Ulrich Sax Matthias Wirth Lena‐Christin Conradi Maximilian Reichert Volker Ellenrieder Philipp Ströbel Michael Ghadimi Marian Grade Dieter Saur Elisabeth Hessmann Günter Schneider |
| author_facet | Constanza Tapia Contreras Jonas Dominik Falke Dana‐Magdalena Seifert Carolin Schneider Lukas Krauß Xin Fang Denise Müller Engin Demirdizen Melanie Spitzner Tiago De Oliveira Christian Schneeweis Jochen Gaedcke Silke Kaulfuß Kimia Mirzakhani Bernd Wollnik Karly Conrads Tim Beißbarth Gabriela Salinas Jonas Hügel Nils Beyer Sophia Rheinländer Ulrich Sax Matthias Wirth Lena‐Christin Conradi Maximilian Reichert Volker Ellenrieder Philipp Ströbel Michael Ghadimi Marian Grade Dieter Saur Elisabeth Hessmann Günter Schneider |
| author_sort | Constanza Tapia Contreras |
| collection | DOAJ |
| description | Pancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C‐inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine‐protein phosphatase non‐receptor type 11 (PTPN11)/Src homology region 2 domain‐containing phosphatase‐2 (SHP2) inhibitors, and broad‐spectrum multi‐kinase inhibitors. Validation in a novel and unique KRASG12C‐mutated patient‐derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C‐inhibitor efficacy, guiding clinical trial design and molecular tumor boards. |
| format | Article |
| id | doaj-art-295a24b42ba8427eb70b2d7d49f89b24 |
| 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-295a24b42ba8427eb70b2d7d49f89b242025-02-04T17:30:20ZengWileyMolecular Oncology1574-78911878-02612025-02-0119229531010.1002/1878-0261.13725KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screeningConstanza Tapia Contreras0Jonas Dominik Falke1Dana‐Magdalena Seifert2Carolin Schneider3Lukas Krauß4Xin Fang5Denise Müller6Engin Demirdizen7Melanie Spitzner8Tiago De Oliveira9Christian Schneeweis10Jochen Gaedcke11Silke Kaulfuß12Kimia Mirzakhani13Bernd Wollnik14Karly Conrads15Tim Beißbarth16Gabriela Salinas17Jonas Hügel18Nils Beyer19Sophia Rheinländer20Ulrich Sax21Matthias Wirth22Lena‐Christin Conradi23Maximilian Reichert24Volker Ellenrieder25Philipp Ströbel26Michael Ghadimi27Marian Grade28Dieter Saur29Elisabeth Hessmann30Günter Schneider31Department of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyInstitute of Pathology University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyInstitute for Translational Cancer Research and Experimental Cancer Therapy Technical University Munich GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyMedical Clinic and Polyclinic II, Klinikum rechts der Isar Technical University Munich GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyInstitute of Pathology University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyInstitute for Translational Cancer Research and Experimental Cancer Therapy Technical University Munich GermanyClinical Research Unit 5002, KFO5002 University Medical Center Göttingen GermanyDepartment of General, Visceral and Pediatric Surgery University Medical Center Göttingen GermanyPancreatic ductal adenocarcinoma (PDAC) has limited treatment options, emphasizing the urgent need for effective therapies. The predominant driver in PDAC is mutated KRAS proto‐oncogene, KRA, present in 90% of patients. The emergence of direct KRAS inhibitors presents a promising avenue for treatment, particularly those targeting the KRASG12C mutated allele, which show encouraging results in clinical trials. However, the development of resistance necessitates exploring potent combination therapies. Our objective was to identify effective KRASG12C‐inhibitor combination therapies through unbiased drug screening. Results revealed synergistic effects with son of sevenless homolog 1 (SOS1) inhibitors, tyrosine‐protein phosphatase non‐receptor type 11 (PTPN11)/Src homology region 2 domain‐containing phosphatase‐2 (SHP2) inhibitors, and broad‐spectrum multi‐kinase inhibitors. Validation in a novel and unique KRASG12C‐mutated patient‐derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRASG12C‐inhibitor efficacy, guiding clinical trial design and molecular tumor boards.https://doi.org/10.1002/1878-0261.13725KRASG12Cpancreatic cancerSHP2SOS1 |
| spellingShingle | Constanza Tapia Contreras Jonas Dominik Falke Dana‐Magdalena Seifert Carolin Schneider Lukas Krauß Xin Fang Denise Müller Engin Demirdizen Melanie Spitzner Tiago De Oliveira Christian Schneeweis Jochen Gaedcke Silke Kaulfuß Kimia Mirzakhani Bernd Wollnik Karly Conrads Tim Beißbarth Gabriela Salinas Jonas Hügel Nils Beyer Sophia Rheinländer Ulrich Sax Matthias Wirth Lena‐Christin Conradi Maximilian Reichert Volker Ellenrieder Philipp Ströbel Michael Ghadimi Marian Grade Dieter Saur Elisabeth Hessmann Günter Schneider KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening Molecular Oncology KRASG12C pancreatic cancer SHP2 SOS1 |
| title | KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening |
| title_full | KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening |
| title_fullStr | KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening |
| title_full_unstemmed | KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening |
| title_short | KRASG12C‐inhibitor‐based combination therapies for pancreatic cancer: insights from drug screening |
| title_sort | krasg12c inhibitor based combination therapies for pancreatic cancer insights from drug screening |
| topic | KRASG12C pancreatic cancer SHP2 SOS1 |
| url | https://doi.org/10.1002/1878-0261.13725 |
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