Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review
Abstract
:1. Introduction
KRAS Molecular Structure, Function, and Mutation
2. Earlier Attempts to Target KRAS-Mutated CRC
3. Direct KRAS Targeting in CRC
3.1. Sotorasib
3.2. Adagrasib
3.3. Comparison between Sotorasib and Adagrasib
3.4. Mechanisms of Resistance to Sotorasib and Adagrasib
4. Future Directions
4.1. Combination with EGFR Inhibitors
4.2. Combination with MEK Inhibitors
4.3. Combination with SOS1 Inhibitors
4.4. Combination with SHP2 Inhibitors
4.5. Newer G12C Inhibitors
4.6. KRAS G12D Targeting
4.7. Tri-Complex and panKRAS Inhibitors
4.8. Other Emerging Therapies
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Glossary
AKT | Protein kinase B (PKB) |
APC | Adenomatous polyposis coli |
BRAF | v-Raf murine sarcoma viral oncogene homolog B1 |
CAR-T | Chimeric antigen receptor (CAR) T-cell |
CDK | Cyclin-dependent kinase |
CI | Confidence interval |
c-MET | c-Mesenchymal-epithelial transition factor |
CNS | Central nervous system |
CRC | Colorectal cancer |
DCC | Deleted in colorectal cancer |
DCR | Disease control rate |
DoR | Duration of response |
EGFR | Epidermal growth factor receptor |
EMA | European Medicines Agency |
ERK | Extracellular signal-regulated kinase |
FAK | Focal adhesion kinase |
FDA | Food and Drug Administration |
FGFR | Fibroblast growth factor receptor |
FOX | Forkhead box |
FTI | Farnesyl transferase inhibitors |
GDP | Guanosine diphosphate |
GRB7 | Growth factor receptor-bound protein 7 |
GTP | Guanosine triphosphate |
HLA | Human leukocyte antigens |
HR | Hazard ratio |
HRAS | Harvey rat sarcoma viral oncogenes |
ICIs | Immune checkpoint inhibitors |
IV | Intravenous |
JAK | Janus kinase |
JNK | c-Jun N-terminal kinase |
KRAS | Kirsten rat sarcoma |
MAPK | Mitogen-activated protein kinase |
MEF | Mouse embryonic fibroblast |
MEK | Mitogen-activated protein kinase |
mTOR | Mammalian target of rapamycin |
MYC | Master regulator of cell cycle entry and proliferative metabolism |
NE | Not evaluable |
NF-κB | Nuclear factor-kappa B |
NR | Not reached |
NRAS | Neuroblastoma rat sarcoma viral oncogenes |
NSCLC | Non-small-cell lung cancer |
ORR | Objective response rate |
OS | Overall survival |
P+D | Placebo + docetaxel |
PD-1 | Programmed death 1 |
PDEδ | Prenyl-binding protein |
PD-L1 | Programmed death ligand 1 |
PFS | Progression-free survival |
PI | Proteasome inhibitor |
PI3K | Phosphatidylinositol 3-kinase |
PLCε | Phospholipase Cε |
RAF | Rapidly accelerated fibrosarcoma |
RAL | Ras-like protein |
RalGDS | RAS-related protein Ral |
RAS | Rat sarcoma |
RHOA | Ras homolog gene family, member A |
ROS1 | Ros proto-oncogene 1 |
RTK | Receptor tyrosine kinase |
S+D | Selumetinib + docetaxel |
SHP2 | Protein tyrosine phosphatase 2 |
S-IIP | Switch-II pocket |
SOS-1 | Son of sevenless homologue 1 |
STAT | Signal transducer and activator of transcription |
TCR | T-cell receptor |
TEAEs | Treatment emergent adverse events |
TP53 | Tumor suppressor protein 53 |
TRAEs | Treatment related adverse events |
VEGF | Vascular endothelial growth factor |
WT | Wild-type |
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Bteich, F.; Mohammadi, M.; Li, T.; Bhat, M.A.; Sofianidi, A.; Wei, N.; Kuang, C. Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review. Int. J. Mol. Sci. 2023, 24, 12030. https://doi.org/10.3390/ijms241512030
Bteich F, Mohammadi M, Li T, Bhat MA, Sofianidi A, Wei N, Kuang C. Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review. International Journal of Molecular Sciences. 2023; 24(15):12030. https://doi.org/10.3390/ijms241512030
Chicago/Turabian StyleBteich, Fernand, Mahshid Mohammadi, Terence Li, Muzaffer Ahmed Bhat, Amalia Sofianidi, Ning Wei, and Chaoyuan Kuang. 2023. "Targeting KRAS in Colorectal Cancer: A Bench to Bedside Review" International Journal of Molecular Sciences 24, no. 15: 12030. https://doi.org/10.3390/ijms241512030