KRASG 12C-inhibitor-based combination therapies for pancreatic cancer: insights from drug screening PMID: 39253995

ADC Targets in Oncology

2026-04-10

KRASG 12C-inhibitor-based combination therapies for pancreatic cancer: insights from drug screening

Mol Oncol. 2024 Sep 10. doi: 10.1002/1878-0261.13725.

Constanza Tapia Contreras ¹ , Jonas Dominik Falke ¹ , Dana-Magdalena Seifert ¹ , Carolin Schneider ¹ , Lukas Krauß ¹ , Xin Fang ¹ , Denise Müller ² , Engin Demirdizen ¹ , Melanie Spitzner ¹ , Tiago De Oliveira ¹ , Christian Schneeweis ³ , Jochen Gaedcke ¹ ⁴ , Silke Kaulfuß ⁴ ⁵ , Kimia Mirzakhani ⁴ ⁵ , Bernd Wollnik ⁴ ⁵ ⁶ , Karly Conrads ⁴ ⁷ , Tim Beißbarth ⁴ ⁷ ⁸ ⁹ , Gabriela Salinas ⁴ ¹⁰ , Jonas Hügel ⁴ ¹¹ , Nils Beyer ⁴ ¹¹ , Sophia Rheinländer ⁴ ¹¹ , Ulrich Sax ⁴ ⁹ ¹¹ , Matthias Wirth ¹ ¹² , Lena-Christin Conradi ¹ ⁴ ⁸ , Maximilian Reichert ¹³ ¹⁴ ¹⁵ ¹⁶ ¹⁷ , Volker Ellenrieder ⁴ ⁸ ¹⁸ , Philipp Ströbel ² ⁴ ⁸ , Michael Ghadimi ¹ ⁸ , Marian Grade ¹ ⁸ , Dieter Saur ³ ¹⁷ , Elisabeth Hessmann ⁴ ⁸ ¹⁸ , Günter Schneider ¹ ³ ⁴ ⁸

Affiliations

1. Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Germany.
2. Institute of Pathology, University Medical Center, Göttingen, Germany.
3. Institute for Translational Cancer Research and Experimental Cancer Therapy, Technical University Munich, Germany.
4. Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Germany.
5. Institute of Human Genetics, University Medical Center Göttingen, Germany.
6. Cluster of Excellence "Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells" (MBExC), University of Göttingen, Germany.
7. Department of Medical Bioinformatics, University Medical Center Göttingen, Germany.
8. CCC-N (Comprehensive Cancer Center Lower Saxony), Göttingen, Germany.
9. Campus-Institute Data Science (CIDAS), Göttingen, Germany.
10. NGS Integrative Genomics Core Unit (NIG), University Medical Center Göttingen (UMG), Germany.
11. Department of Medical Informatics, University Medical Center, Göttingen, Germany.
12. Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Germany.
13. Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, Germany.
14. Translational Pancreatic Research Cancer Center, Medical Clinic and Polyclinic II, Klinikum rechts der Isar, Technical University Munich, Germany.
15. Center for Protein Assemblies (CPA), Technical University of Munich, Garching, Germany.
16. Center for Organoid Systems and Tissue Engineering (COS), Technical University Munich, Garching, Germany.
17. German Cancer Consortium (DKTK), Partner Site Munich, a Partnership Between DKFZ and University Hospital Klinikum rechts der Isar, Munich, Germany.
18. Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Germany.

Abstract

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^G12C 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^G12C-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^G12C-mutated patient-derived Organoid model confirmed the described hits from the screening experiment. Our findings propose strategies to enhance KRAS^G12C-inhibitor efficacy, guiding clinical trial design and molecular tumor boards.

Keywords

KRASG12C; SHP2; SOS1; pancreatic cancer.