Glucose conditions influence CAMKK2-targeted therapy sensitivity in triple-negative breast cancer of different ancestry

Background: Triple-negative breast cancer (TNBC) is associated with a higher incidence and mortality in women with specific metabolic comorbidities, including obesity, diabetes, and dyslipidemia. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) is a central kinase regulating cellular energy metabolism and stress adaptation in TNBC cells. This study examines how different glucose conditions affect the survival and response of TNBC cell lines to CAMKK2 inhibitors. Methods: A panel of commonly used TNBC cell lines (MDA MB 231, MDA MB 468, MDA MB 157, HCC1806) were treated with STO 609 and SGC CAMKK2 1 at various glucose levels. Cells were incubated under four glucose conditions, 0.33 mM (severe hypoglycemia), 5 mM (physiological/normal), 17.5 mM (moderate hyperglycemia), and 50 mM (extreme hyperglycemia). IC₅₀ values and cell viability were assessed following drug treatment across these conditions. Results and Conclusion: In all cell lines, results indicated an overall increase in IC₅₀ (reduced inhibitor sensitivity) as glucose levels changed from moderate (5, 17.5 mM) to either low (0.33 mM) or high (50 mM). For STO-609, IC₅₀ values improved from 71-2533 µM at 0.33 mM to 32-91 µM at 17.5 mM but increased again to 92-894 µM at 50 mM. With SGC-CAMKK2-1, IC₅₀ ranged from 112-619 µM at 0.33 mM to 48-148 µM at 17.5 mM and increased again to 154-520 µM at 50 mM. Notably, HCC1806 cells were the most sensitive to both CAMKK2 inhibitors, while MDA MB 157 was overall more resistant. Different glucose conditions have a significant impact on the efficacy of CAMKK2-targeted inhibitors in TNBC, with some cell lines displaying more metabolic sensitivity than others. These findings demonstrate that personalized therapeutic strategies, considering the metabolic background, may improve treatment outcomes in aggressive breast cancers.