Hyperglycemia–Lactate Crosstalk in DDR: A metabolic axis that disables checkpoints and tilts repair toward HR-mediated chemoresistance

Model diabetic tumor microenvironments by culturing cancer and normal epithelial cells in high glucose and high lactate, then measure CHK1 activation, NBS1 K388 lactylation, MRN assembly, and HR vs end-joining ratios using reporters and repair-seq. Test whether LDHA inhibition (stiripentol) or TIP60/HDAC3 modulation reverses the HR bias and restores checkpoint proficiency. Evaluate genotype interactions (BRCA1/WWOX status) to see whether certain tumors are especially susceptible to metabolic pathway steering. This connects two “unexpected” metabolic effects on DDR into a single testable model of pathway dominance; brings in pathway hierarchy concepts and clinically actionable levers. It offers an explanation for higher mutation rates yet treatment resistance in diabetic settings, and suggests simple metabolic co-therapies to sensitize tumors or protect normal tissues depending on context. The impact is metabolically informed precision radiochemotherapy, with biomarkers (lactate, NBS1 lactylation, glucose) guiding adjuvant interventions.

References:

1. NBS1 lactylation is required for efficient DNA repair and chemotherapy resistance. Hengxing Chen, Yun Li, Hua-fu Li, Xiancong Chen, Hua-Feng Fu, Deli Mao, Wei Chen, Linxiang Lan, Chun-ming Wang, K. Hu, Jia Li, Chengming Zhu, I. Evans, Eddie Cheung, Daning Lu, Yulong He, Axel Behrens, Dong Yin, Changhua Zhang (2024). Nature.
2. Unveiling the relationship between WWOX and BRCA1 in mammary tumorigenicity and in DNA repair pathway selection. Tirza Bidany-Mizrahi, Aya Shweiki, Kian Maroun, Lina Abu-Tair, Bella Mali, R. Aqeilan (2024). Cell Death Discovery.
3. Aberrant DNA damage response and DNA repair pathway in high glucose conditions.. Amy Zhong, Melissa H Y Chang, T-H Yu, Raymond Gau, D. Riley, Yumay Chen, Phang-lang Chen (2018). Journal of Cancer Research Updates.