2. Academic Validation
  3. Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells

Simultaneous targeting of KRAS and CDK4 synergistically induces durable growth arrest in pancreatic cancer cells

  • Cell Death Dis. 2025 Dec 23. doi: 10.1038/s41419-025-08362-w.
Maj-Britt Paulsohn 1 2,  Klara Henrike Frahnert 1,  Denise Schlösser 2 3,  Joana Oschwald 2 3,  Waltraut Kopp 2 3,  Xin Fang 4,  Carolin Schneider 2 4,  Constanza Tapia Contreras 2 4,  Adi Danieli-Mackay 2 5,  Fabian Ludewig 6,  Martina Bleyer 7,  Gabriela Salinas 2 5 6,  Günter Schneider 2 4 8,  Elisabeth Hessmann 2 3,  Matthias Dobbelstein 9 10 11
Affiliations

Affiliations

  • 1 Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany.
  • 2 Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Germany.
  • 3 Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany.
  • 4 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany.
  • 5 Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
  • 6 NGS-Integrative Genomics (NIG), University Medical Center Göttingen, Göttingen, Germany.
  • 7 Laboratory Animal Science Unit, Pathology, German Primate Center, Leibniz Institute of Primate Research, Göttingen, Germany.
  • 8 CCC-N (Comprehensive Cancer Center Lower Saxony), Göttingen, Germany.
  • 9 Department of Molecular Oncology, Göttingen Center of Molecular Biosciences (GZMB), University Medical Center Göttingen, Göttingen, Germany. [email protected].
  • 10 Clinical Research Unit 5002, KFO5002, University Medical Center Göttingen, Göttingen, Germany. [email protected].
  • 11 Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany. [email protected].
PMID: 41436723 DOI: 10.1038/s41419-025-08362-w
Abstract

Mutant Ras oncoproteins, particularly KRAS, are among the most prevalent drivers of Cancer. Small-molecule KRAS inhibitors have emerged as promising Cancer therapeutics, yet resistance development remains a major hurdle. To overcome this challenge, we explored rational combination strategies aimed at enhancing therapeutic efficacy and durability. We show that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS-G12C mutations. This synergy was especially pronounced following drug washout, indicating a durable cellular response. Similar synergistic effects were observed in non-small-cell lung Cancer (NSCLC) cells. Additionally, the KRAS-G12D inhibitor MRTX1133 cooperated with Palbociclib to suppress growth of KRAS-G12D-mutant PDAC cells. Mechanistically, the combinations induced sustained cell cycle arrest, marked by reduced RB phosphorylation, decreased E2F1 expression, and increased levels of CDKN1B/p27. Deletion of CDKN1B largely reversed the growth-inhibitory effect, highlighting its essential role in mediating the observed synergy. In an orthotopic, immunocompetent mouse model of PDAC, MRTX1133 significantly reduced tumor growth and extended survival; however, despite its ability to suppress RB phosphorylation, Palbociclib failed to enhance these effects. Single-cell RNA Sequencing suggested that Palbociclib treatment induces tumor vascularization, perhaps contributing to the lack of drug synergy observed in vivo. In summary, our findings demonstrate the therapeutic potential of enhancing cell cycle restriction point activation in KRAS inhibitor-based therapies, while emphasizing the importance of placing combination therapies into a suitable context.

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