<scp>KRAS<sup>G</sup></scp><sup>12<scp>C</scp></sup>‐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 treatment, particularly those targeting the KRAS<sup>G12C</sup> 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 KRAS<sup>G12C</sup>-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 KRAS<sup>G12C</sup>-mutated patient-derived organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRAS<sup>G12C</sup>-inhibitor efficacy, guiding clinical trial design and molecular tumor boards.
Authors
- Constanza Tapia Contreras (ORCID: https://orcid.org/0000-0003-2054-0963)
- Michael B. Ghadimi (ORCID: https://orcid.org/0000-0001-8208-1526)
- Lukas Krauß (ORCID: https://orcid.org/0000-0003-0062-8685)
- Matthias Wirth (ORCID: https://orcid.org/0000-0002-8340-0872)
- Ulrich Sax (ORCID: https://orcid.org/0000-0002-8188-3495)
- Tim Beißbarth (ORCID: https://orcid.org/0000-0001-6509-2143)
- Denise Müller (ORCID: https://orcid.org/0000-0001-6231-7431)
- Jochen Gaedcke (ORCID: https://orcid.org/0000-0002-6130-5874)
- Lena‐Christin Conradi (ORCID: https://orcid.org/0000-0002-9488-1018)
- Philipp Ströbel (ORCID: https://orcid.org/0000-0002-8528-8060)
- Silke Kaulfuß (ORCID: https://orcid.org/0000-0003-2577-9711)
- Christian Schneeweis
- Melanie Spitzner (ORCID: https://orcid.org/0000-0002-3673-0625)
- Marian Grade
- Elisabeth Heßmann (ORCID: https://orcid.org/0000-0002-9462-1291)
- Volker Ellenrieder (ORCID: https://orcid.org/0000-0001-9981-8571)
- Carolin Schneider (ORCID: https://orcid.org/0000-0003-3539-9026)
- Tiago De Oliveira (ORCID: https://orcid.org/0000-0002-2502-7897)
- Jonas Hügel (ORCID: https://orcid.org/0000-0002-4183-1287)
- Maximilian Reichert (ORCID: https://orcid.org/0000-0002-8611-5639)
- Kimia Mirzakhani
- Xin Fang (ORCID: https://orcid.org/0000-0002-8561-1518)
- Engin Demirdizen
- Gabriela Salinas (ORCID: https://orcid.org/0000-0001-8269-2669)
- Bernd Wollnik (ORCID: https://orcid.org/0000-0003-2589-0364)
- Günter Schneider (ORCID: https://orcid.org/0000-0003-1840-4508)
- Sophia Rheinländer (ORCID: https://orcid.org/0000-0002-5406-4427)
- Karly Conrads (ORCID: https://orcid.org/0009-0006-4536-8564)
- Dieter Saur (ORCID: https://orcid.org/0000-0001-5874-0210)
- Jonas Dominik Falke
- Dana‐Magdalena Seifert
- Nils Beyer
Institutions
- German Cancer Research Center (DE)
- TUM Klinikum (DE)
- Humboldt-Universität zu Berlin (DE)
- Universitätsmedizin Göttingen (DE)
- Institute of Clinical Cancer Research (DE)
- Nanoscale Microscopy and Molecular Physiology of the Brain Cluster of Excellence 171 — DFG Research Center 103 (DE)
- Technical University of Munich (DE)
- University of Göttingen (DE)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Molecular Oncology
- Published
- 2024-09-10
- DOI
- https://doi.org/10.1002/1878-0261.13725
- Citations
- 10
- Primary Topic
- Protein Tyrosine Phosphatases
- Type
- article
- Field-Weighted Citation Impact
- 2.34
Funders
- Wilhelm Sander-Stiftung
- Deutsche Forschungsgemeinschaft
- Volkswagen Foundation
- Bundesministerium für Bildung und Forschung
- Deutsche Krebshilfe
- Deutschen Konsortium für Translationale Krebsforschung
- Bayerische Staatsministerium für Wirtschaft, Landesentwicklung und Energie