Key Points
• Combined therapy with pemetrexed (MTA) and cisplatin in patients with advanced non-small cell lung cancer is the standard of care, however the 5-year survival rate is fewer than 10% due to resistance. In the current study, researchers intended to identify and manipulate chemotherapy-induced metabolic adaptation in target resistance cancer cells.
• Important enzymes in the pyrimidine salvage pathway include cytidine deaminase (CDA) and thymidine phosphorylase (TYMP). Of note, 5′-deoxy-5-fluorocytidine (5′-DFCR) is a cytidine analogue, which is converted first by CDA and then by TYMP into 5-fluorouracil, which is used for chemotherapy of solid tumors.
• The researchers developed a small-scale screen of mitochondrial metabolism inhibitors. This screen showed that 5′-DFCR selectively targets chemotherapy-resistant A549 paraclone cells characterized by high CDA and TYMP expression. CDA and TYMP expression was further boosted by chemotherapy in cell line A549. This outcome was also noted in the KRAS-addicted NSCLC cell lines H358 and H411.’
• The authors wrote, “The addition of 5′-DFCR on the second day after MTA and cisplatin combination therapy was the most efficient treatment to eradicate chemotherapy-resistant NSCLC cells. Moreover, recovery from treatment-induced DNA damage was delayed and accompanied by senescence induction and acquisition of a hybrid-EMT phenotype. In a subset of patient tumors, CDA expression was also increased after treatment with neoadjuvant chemotherapy”
• Per the authors, one limitation of the study is that they investigated a limited number of possible combinations of the triple combination therapy, with the exact treatment schedule on the treatment efficiency needing to be explored more robustly.