Table 3.
Synthetic Lethality and Regulators of Ferroptosis.
| Author | Synthetic Lethal Factors (A) | Synthetic Lethal Factors (B) | RAS Mutation | Summary of Synthetic Lethality | Tissues and Cells | Verification of Ferroptosis | Other Type of Cell Death | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Increase in Intracellular Reactive Oxygen Species and Lipid Peroxides | Intracellular Iron Accumulation/Inhibition by Iron Chelators | Cell Death by Ferotosis Inducer | Morphological Changes Characteristic of Ferroptosis | Bioenergetic Changes: Intracellular ATP Depletion | Lack of Other PCD Features | Escape of Cell Death by Ferroptosis Inhibitors | |||||||
| Yang, W.S., et al. [13] | RSL3, ML162, anf DPI10 | oncogenic-HRAS | RSL3, ML162, and DPI10 induce ferroptosis in engineered oncogenic-RAS fibroblast-derived tumorigenic cell lines | oncogenic-HRAS cells, 117 human cancer cell lines | ○ | ○ | ○ | ||||||
| Yu, Y., et al. [51] | Erastin | Cytarabine and Doxorubicin | Erastin induces cell death in AML cells in a dose-dependent manner through a mixture of ferroptosis, apoptosis, necroptosis, and autophagy. | HL-60 cells (AML, NRAS_Q61L) | mixed types of cell death associated with ferroptosis, apoptosis, necroptosis, and autophagy | ||||||||
| Chio, I.I.C., et al. [46] | MK 2206 (pan-AKT inhibitor) | BSO | oncogenic-KRAS | Combined targeting of AKT and glutathione synthesis inhibits pancreatic cancer | human and mouse Kras mutant PDA cells, Suit2 xenograft model | ○ | |||||||
| Kerins, M.J., et al. [52] | Erastin, RSL3, ML162, glutamate | FH deficiency | Ferroptosis inducers are selectively toxic to FH−/− cell line UOK262, because C93 of GPX4 is post-translationally modified by fumarates that accumulate in conditions of FH−/−, and C93 modification represses GPX4 activity. | HK2 fumarate hydratase knockout cell lines | ○ | ○ | ○ | ||||||
| Okazaki, S., et al. [53] | Sulfasalazine (xc- inhibitor) | Dyclonine (oral anesthetics) | Sulfasalazine-resistant head and neck squamous cell carcinoma (HNSCC) cells highly express ALDH3A1 and knockdown of ALDH3A1 sensitized these cells to sulfasalazine. The combination of dyclonine and sulfasalazine cooperatively suppressed the growth of highly ALDH3A1-expressing HNSCC or gastric tumors that were resistant to sulfasalazine monotherapy. |
Sulfasalazine-resistant human HNSCC cells | non-programmed cell death | ||||||||
| Bersuker, K., et al. [28] | RSL3 | FSP1 | In CRISPR-Cas9 screening, RSL3 induces synthetic lethality in U-2 OS FSP1 knockout cell lines. FSP1 acts parallel to GPX4 to inhibit ferroptosis. | U-2 OS FSP1 knockout cell lines | ○ | ||||||||
| Ogiwara, H., et al. [54] | GCL catalytic subunit (GCLC) | ARID1A deficiency | Cancer cells lacking ARID1A are specifically vulnerable to glutathione and inhibition of GCLC. | ARID1A-knockout HCT116 colon cancer cells | apoptosis | ||||||||
| To, T.L., et al. [55] | GPX4 | Mitochondrial Inhibitors (antimycin, oligomycin, ethidium bromide) | Genome-wide CRISPR screening using small molecule mitochondrial inhibitors showed that genes involved in the glycolytic system (PFKP), pentose phosphate pathway (G6PD), and defense against lipid peroxidation (GPX4) were closely associated with synthetic lethality. | K562, HAP1, HeLa | ○ | ○ | |||||||
| Hu, K., et al. [22] | SLC7A10 | oncogenic-KRAS | In KRAS-mutant lung adenocarcinoma transplanted mice, treatment with SLC7A11 inhibitor (HG106) resulted in tumor suppression and prolonged survival. | KRAS-mutant lung adenocarcinoma cells, preclinical lung cancer mouse model | apoptosis | ||||||||
| Kwon, O.S., et al. [47] | Erastin | oncogenic-RAS | Erastin is a synthetic lethal compound against cancer expressing an oncogenic RAS. The activity of transcription factors, including NRF2 and AhR, serve as important markers of erastin resistance. | mesenchymal lung cancer cell lines | ○ | ○ | ○ | ||||||
| Sugiyama, A., et al. [49] | Sulfasalazine (xc- inhibitor) | JNK (RAS effector) activation | Sulfasalazine is highly cytotoxic in paclitaxel-resistant uterine serous carcinoma. Interaction of ROS accumulation and JNK pathway activation increases susceptibility to SAS-induced ferroptosis. | human uterine serous carcinoma cell lines | ○ | ○ | |||||||
| Yusuf, R.Z., et al. [50] | RSL3, GPX4 knock down | Aldh3a2 inhibition | Aldh3a2 inhibition in combination with GPX4 inhibition leads to synthetic lethality in mouse and human AML cells. | human AML cells, Aldh-mut and Aldh-Ctrl mice were used to generate MLL-AF9 leukemia through retroviral transduction | ○ | ○ | ○ | ||||||
| Baird, L., et al. [56] | NRF2 | 17-AAG, 17-DMAG, IPI-504 | 17-AAG is synthetic lethal with NRF2 in human cancer cell lines | Keap1 knockout cells | No description of what type of cell death. | ||||||||
| Joly, J. H., et al. [57] | GSH | GLUT1 | Co-targeting GLUT1 and GSH synthesis induces synthetic lethal cell death in high xCT-expressing cell lines susceptible to glucose deprivation | xCT-high cell lines of glioblastoma and Ewing’s sarcoma | No description of what type of cell death. | ||||||||
| Lorenzato, A., et al. [58] | vitamine C | Cetuximab | The combination of vitamin C and cetuximab causes synthetic lethality triggered by ATP depletion and oxidative stress. This in turn suppresses the acquisition of resistance to anti-EGFR antibodies. | Advanced colorectal cancer patient-derived xenografts | ○ | ○ | ○ | ○ | |||||
| Verma, N., et al. [59] | Ferroptosis inducers (FIN56, erastin) | BET inhibitor (JQ1) + proteasome inhibitor (BTZ) | Co-inhibition of BET (bromodomain and extra-terminal) and proteasome induces ferotosis and synthetic lethality in triple-negative breast cancer (TNBC) cell lines. | TNBC cell lines | ○ | ○ | |||||||
| Baird, L. and M. Yamamoto. [60] | NRF2 | Mitomycin C | Aberrant NRF2 activation confers enhanced mitomycin C sensitivity in human cancer cell lines | NRF2-activated human cancer cells | No description of what type of cell death. | ||||||||
| Chen, S., et al. [61] | erastin | AOAA | AOAA and Erastin resulted in synthetic lethality both in vitro and in vivo, which was mediated through increased ferroptosis and apoptosis. | Tissue microarrays of colorectal cancer | apoptosis + ferroptosis | ||||||||
| Singhal, R., et al. [62] | Erastin, RSL3, DMF | HIF-2α | Ferroptosis inducer (Erastin, RSL3) and DMF led to selective synthetic lethality in HIF-2a expressing tumor enteroids. | colon cancer cells and colon tumors in mice | ○ | ○ | ○ | ○ | |||||
ATP, Adenosine tri-phosphate; PCD, Programmed cell death; AML, acute myeloid leukemia; BSO, L-Buthionine-(S,R)-Sulfoximine; PDA, Pancreatic ductal carcinoma; GCL, Glutamate cysteine ligase; MLL, Mixed lineage leukemia; BET, bromodomain and extra-terminal; BTZ, bortezomib; AOAA, Aminooxyacetic acid; DMF, N,N-dimethylformamide; HIF-2α, hypoxia-inducible factor 2α. ○, applicable; blank, not applicable.