Table 1.
Proposed combination therapy strategies with nucleotide synthesis inhibitors
| Combination agent (target) | Mechanism | Cancer type | Validation level |
|---|---|---|---|
| Dihydroorotate dehydrogenase | |||
| Gemcitabine (ribonucleotide reductase inhibitor and DNA chain terminator) | Decreased molecular competition by endogenous dCTP | PDAC11 | Animal models |
| Doxorubicin (topoisomerase II inhibitor) | Impaired DNA repair | TNBC9 | Animal models |
| Floxuridine (5-FU prodrug, TS inhibitor) | Unknown | KRAS-mutant PDAC5 | Cell culture |
| Cisplatin/etoposide (alkylating agent/topoisomerase II inhibitor) | Unknown | SCLC2 | Animal models |
| Azacytidine (DNMT1 inhibitor) | Decreased molecular competition by endogenous dCTP | MDS131 | Animal models |
| Dipyridamole (ENT1/2 inhibitor) | Enhanced (d)NTP depletion | CRC144, neuroblastoma145, AML146 | Cell culture, animal models |
| ENT1 knockout | Enhanced (d)NTP depletion | PDAC149 | Animal models |
| GPX4 inhibitor (ferroptosis inducer) | Increased mitochondrial lipid peroxidation | Multiple139 | Animal models |
| Deoxycytidylate deaminase knockout | Combinatorial dUMP depletion and dTTP depletion | SCLC2 | Cell culture |
| TRAIL (apoptosis inducer) | Decreased mitochondrial membrane potential | Multiple141 | Cell culture |
| Buparlisib (PI3K inhibitor) | Combinatorial de novo pathway blockade | GBM with PTEN deletion7 | Animal models |
| Lapatinib (EGFR inhibitor) | Combinatorial de novo pathway blockade | GBM with EGFR amplification7 | Animal models |
| Prednisolone (glucocorticoid receptor agonist) | Unknown | KRAS-mutant PDAC5 | Cell culture |
| Thapsigargin (ER stress inducer) | Depleted deoxyuridine, leading to amplified ER stress and ROS | PDAC78 | Cell culture |
| TS | |||
| Carboplatin (alkylating agent) | Unknown | NSCLC112 | FDA approved |
| Pembrolizumab (PD1 blockade) | Immunogenic cell death, enhanced T cell OXPHOS | NSCLC111,112 | FDA approved |
| Inosine monophosphate dehydrogenases 1 and 2 | |||
| Radiation therapy | Inhibited radiation therapy-induced DNA double-strand break repair | GBM136 | Animal models |
| Temozolomide (alkylating agent) | Increased salvage of methylated O6-MG nucleobases leading to increased O6-MG incorporation into DNA | GBM134 | Animal models |
| Anti-PD1 antibody | Increased cancer cell presentation of immunogenic antigens via MHC class I | TNBC119 | Animal models |
| Ribonucleotide reductase | |||
| DI-39/VE-822 (DCK inhibitor/ATR inhibitor) | Combined dCTP depletion and replication stress | B-ALL60,156 | Animal models |
5-FU, 5-fluorouracil; AML, acute myeloid leukaemia; B-ALL, B cell acute lymphoblastic leukaemia; CRC, colorectal cancer; DCK, deoxycytidine kinase; dCTP, deoxycytidine triphosphate; (d)NTP, (deoxy)nucleotide triphosphate; dTTP, deoxythymidine triphosphate; dUMP, deoxyuridine monophosphate; ENT1/2, equilibrative nucleoside transporters 1 and 2; ER, endoplasmic reticulum; GBM, glioblastoma multiforme; MDS, myelodysplastic syndrome; NSCLC, non-small-cell lung cancer; O6-MG, O6-methylguanine; OXPHOS, oxidative phosphorylation; PDAC, pancreatic ductal adenocarcinoma; ROS, reactive oxygen species; SCLC, small-cell lung cancer; TNBC, triple-negative breast cancer; TRAIL, TNF-related apoptosis-inducing ligand; TS, thymidylate synthase.