2025/07/22 by Míriam Tarrado‐Castellarnau, Carles Foguet, Josep Tarragó‐Celada +11 · 1 voice
Biochemistry, Genetics and Molecular Biology · Medicine · #Advanced Breast Cancer Therapies #Metabolism, Diabetes, and Cancer #Pancreatic function and diabetes
paper · pdf · doi:10.1038/s41388-025-03495-w
openalex publication_date 2025/07/22 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
Several mechanisms of resistance of cancer cells to cyclin-dependent kinase inhibitors (CDKi) have been identified, including the upregulation of metabolic regulators such as glutaminase. However, whether such resistance mechanisms represent optimal targets has not been determined. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDKi selectively targeting CDK4/6, or Telaglenastat, a selective glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenastat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenastat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenastat. In conclusion, combination with Telaglenastat optimally forestalls acquired resistance to Palbociclib in cancer cells.