KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance
Abstract
:1. Introduction
1.1. KRAS Structure and Function
1.2. KRAS Activity Is Regulated at Multiple Levels
1.3. KRAS Regulates Growth through Multiple Mechanisms
1.4. Impact of KRAS on Metabolic Processes
1.5. KRAS Mutations
2. Targeted KRAS Inhibitors
2.1. KRAS as a Therapeutic Target
2.2. KRAS G12C-Selective Covalent Inhibitors
2.3. KRAS G12D Inhibitors
2.4. KRAS G12S and KRAS G12R Tool Compounds
2.5. Pan-KRAS Inhibitors
2.6. Cyclophilin A Recruitment
2.7. siRNAs
2.8. Peptide Nucleic Acids
2.9. Destabilizing and Degrading Agents
3. KRAS-Dependent Immunotherapies
3.1. Mutant KRAS Vaccines
3.2. Bispecific T-Cell Engagers
3.3. Adoptive Immunotherapies
4. Mutational Resistance
4.1. Resistance to KRAS Inhibitors
4.2. Drug Resistant Mutations to KRASi
4.3. Copy Number Alterations in KRAS
4.4. Resistance Caused by Other Genes
5. Non-Mutational Resistance
5.1. Rapid Adaptive Resistance
5.2. Reactivation of the RAS Pathway or Alternative Signaling
5.3. Epithelial-to-Mesenchymal Transition
5.4. Tumor Microenvironment
5.5. Drug Efflux Pumps
5.6. Combination Therapies
6. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Glossary
4EBP1 | Eukaryotic Translation Initiation Factor 4E Binding Protein 1, encoded by the gene EIF4EBP1. |
ALK | ALK Receptor Tyrosine Kinase, also known as Anaplastic Lymphoma Kinase. |
Amplification | An increase in the number of copies in a region of the genome. |
APC | APC Regulator Of WNT Signaling Pathway, also known as Adenomatous Polyposis Coli. |
ARAF | A-Raf Proto-Oncogene, Serine/Threonine Kinase. |
ARF | One of the proteins encoded by the gene Cyclin Dependent Kinase Inhibitor 2A, or CDKN2A. Also known as p19-ARF. |
AURKA | Aurora Kinase A. |
BiTE | Bispecific T-cell engager. |
BRAF | B-Raf Proto-Oncogene, Serine/Threonine Kinase. |
CAB39 | Calcium-Binding Protein 39. |
CAS9 | CRISPR-associated protein 9, used together with CRISPR to cleave DNA. |
CCL2 | C-C Motif Chemokine Ligand 2. |
CDK4 | Cyclin-Dependent Kinase 4. |
CDK6 | Cyclin-Dependent Kinase 6. |
CDKN2A | Cyclin-Dependent Kinase Inhibitor 2A, encodes p16-INK4A and ARF. |
CDKN2B | Cyclin-Dependent Kinase Inhibitor 2B |
COVID-19 | Coronavirus disease of 2019, caused by the virus SARS-CoV-2 |
CRAF | Raf-1 Proto-Oncogene, Serine/Threonine Kinase, also known as RAF1. |
CRC | Colorectal carcinoma or colorectal cancer. |
CRISPR | Clustered Regularly Interspaced Short Palindromic Repeats, often used to knock out a gene of interest. |
CRISPRi | Inhibitory form of CRISPR that uses dead Cas9 deficient at cutting DNA to recruit negative regulatory transcription factors to the promoter of a gene of interest. |
CTLA-4 | Cytotoxic T-Lymphocyte-Associated Protein 4, an immune checkpoint protein. |
CTNNB1 | Catenin Beta 1, also known as β-catenin. |
CYCA | Cyclophilin A. |
Cyclins | A family of proteins that bind to cyclin-dependent kinases and regulate cell cycle. |
DC | Dendritic cell. |
DTP | Drug tolerant persister cells. |
DUSPs | Dual-Specificity Phosphatase protein family. |
E2F | E2F Transcription Factor. |
EGF | Epidermal Growth Factor. |
EGFR | Epidermal Growth Factor Receptor. |
EMT | Epithelial-to-mesenchymal transition. |
ERK1 | Mitogen-Activated Protein Kinase 3, also known as Extracellular Signal-Regulated Kinase 1, a protein encoded by the gene MAPK3. |
ERK2 | Mitogen-Activated Protein Kinase 2, also known as Extracellular Signal-Regulated Kinase 2, a protein encoded by the gene MAPK1. |
FDA | United States Food and Drug Administration. |
FGFR | Fibroblast Growth Factor Receptor 1. |
G12Ci | An inhibitor that is selective for KRAS with the 12th amino acid altered from glycine to cysteine. |
GAB1 | GRB2-associated binding protein 1. |
GAP | GTPase-activating protein, promotes hydrolysis of GTP to GDP |
GDP | Guanosine diphosphate. KRAS is inactive when bound to GDP. |
GEF | Guanine nucleotide exchange factor, promotes exchange of GDP to GTP |
GM-CSF | Granulocyte-macrophage colony-stimulating factor, also known as colony-stimulating factor 2. |
GRB2 | Growth Factor Receptor Bound Protein 2. |
GTP | Guanosine triphosphate. KRAS is active when bound to GTP. |
HDAC5 | Histone Deacetylase 5. |
HLA | Human leukocyte antigens. |
HRAS | HRas Proto-Oncogene, GTPase, also known as Harvey Rat Sarcoma Viral Oncoprotein. |
ICMT | Isoprenylcysteine Carboxyl Methyltransferase. |
IDH1 | Isocitrate Dehydrogenase (NADP(+)) 1. |
IDH2 | Isocitrate Dehydrogenase (NADP(+)) 2. |
IRE1α | Endoplasmic Reticulum To Nucleus Signaling 1, encoded by the gene ERN1. |
KEAP1 | Kelch-Like ECH-Associated Protein 1. |
KRAS | KRAS Proto-Oncogene, GTPase, also known as Kirsten Rat Sarcoma Viral Proto-Oncogene and also abbreviated at K-Ras. |
KRASi | An entity that inhibits KRAS. |
KSR | Kinase Suppressor Of Ras 1, encoded by the gene KSR1. |
MDR1 | ATP-Binding Cassette Subfamily B Member 1, also known as Multidrug Resistance Protein 1, encoded by the gene ABCB1. |
MEK | Mitogen-Activated Protein Kinase Kinase 1, encoded by the gene MAP2K1. |
MET | MET Proto-Oncogene, Receptor Tyrosine Kinase. |
MHC | Major histocompatibility complex. |
MRAS | Muscle RAS Oncogene Homolog. |
mTCR | Murine T-cell receptor. |
mTOR | Mechanistic Target Of Rapamycin Kinase. |
MYC | MYC Proto-Oncogene, BHLH Transcription Factor, also known as c-MYC and as Avian Myelocytomatosis Viral Oncogene Homolog. |
NF1 | Neurofibromatosis type 1. |
NRAS | NRAS Proto-Oncogene, GTPase, also known as Neuroblastoma RAS Viral (V-Ras) Oncogene Homolog. |
NSCLC | Non-small cell lung cancer. |
p53 | Tumor Protein P53, encoded by the gene TP53. |
PD-1 | Programmed Cell Death Protein 1. |
PDAC | Pancreatic ductal adenocarcinoma. |
PD-L1 | CD274 Molecule, also known as Programmed Cell Death 1 Ligand 1, encoded by the gene CD274. |
PTCH1 | Patched 1. |
SHP2 | Protein Tyrosine Phosphatase Non-Receptor Type 11, encoded by the gene PTPN11. |
PBL | Peripheral blood lymphocytes. |
PIK3CA | Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha, also known as PtdIns-3-Kinase Subunit P110-Alpha, encodes the p110α subunit of PI3K. |
PIP2 | Phosphatidylinositol 4,5-bisphosphate. |
PIP3 | Phosphatidylinositol-3,4,5-triphosphate. |
PNA | Peptide nucleic acid, a synthetic molecule hybridizing DNA bases with a peptide polymer chain. |
PREX1 | Phosphatidylinositol-3,4,5-Trisphosphate Dependent Rac Exchange Factor 1. |
PROTAC | Proteolysis targeting chimeras containing a domain binding the protein of interest linked to a domain that recruits an E3 ubiquitin ligase. |
PTEN | Phosphatase And Tensin Homolog, also known as Phosphatidylinositol 3,4,5-Trisphosphate 3-Phosphatase And Dual-Specificity Protein Phosphatase PTEN. |
RAB | RAB1A, Member of RAS Oncogene Family. |
RAN | RAN, Member of RAS Oncogene Family. |
RAS-GAP | RAS P21 Protein Activator 1, also known as p120GAP, encoded by the gene RASA1. |
RB1 | RB Transcriptional Corepressor 1, also known as Retinoblastoma 1. |
RCE1 | Ras Converting CAAX Endopeptidase 1. |
RET | Ret Proto-Oncogene, also known as Rearranged During Transfection. |
RGS | Regulator Of G Protein Signaling. |
RHO | Rhodopsin. |
RICTOR | RPTOR Independent Companion Of MTOR Complex 2. |
RSK1 | Ribosomal Protein S6 Kinase A1. |
S6 | Ribosomal Protein S6. |
SARS-CoV-2 | Severe acute respiratory syndrome coronavirus 2, the virus that causes COVID-19. |
SHOC2 | SHOC2 Leucine Rich Repeat Scaffold Protein. |
siRNA | Small interfering ribonucleic acid, used to decrease expression of target messenger RNAs. |
SMARCA4 | SWI/SNF Related, Matrix Associated, Actin-Dependent Regulator Of Chromatin, Subfamily A, Member 4. |
SOS1 | SOS Ras/Rac Guanine Nucleotide Exchange Factor 1, also known as Son Of Sevenless Homolog 1. |
SPRED1 | Sprouty-Related EVH1 Domain Containing 1. |
SPRY1 | Sprouty RTK Signaling Antagonist 1. |
Synthetic lethal/collateral dependency | Two genes whose alterations are lethal to cells only when they are in combination. |
TCR | T-cell receptor. |
TEAD | TEA Domain Transcription Factor 1. |
TGFβ | Transforming Growth Factor Beta 1. |
TME | Tumor microenvironment. |
TSC1 | TSC Complex Subunit 1, also known as Tuberous Sclerosis 1 Protein. |
TSC2 | TSC Complex Subunit 2, also known as Tuberous Sclerosis 2 Protein. |
UGP2 | UDP-Glucose Pyrophosphorylase 2. |
VEGF | Vascular Endothelial Growth Factor. |
YAP | Yes1-Associated Transcriptional Regulator. |
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Ash, L.J.; Busia-Bourdain, O.; Okpattah, D.; Kamel, A.; Liberchuk, A.; Wolfe, A.L. KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance. Curr. Oncol. 2024, 31, 2024-2046. https://doi.org/10.3390/curroncol31040150
Ash LJ, Busia-Bourdain O, Okpattah D, Kamel A, Liberchuk A, Wolfe AL. KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance. Current Oncology. 2024; 31(4):2024-2046. https://doi.org/10.3390/curroncol31040150
Chicago/Turabian StyleAsh, Leonard J., Ottavia Busia-Bourdain, Daniel Okpattah, Avrosina Kamel, Ariel Liberchuk, and Andrew L. Wolfe. 2024. "KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance" Current Oncology 31, no. 4: 2024-2046. https://doi.org/10.3390/curroncol31040150
APA StyleAsh, L. J., Busia-Bourdain, O., Okpattah, D., Kamel, A., Liberchuk, A., & Wolfe, A. L. (2024). KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance. Current Oncology, 31(4), 2024-2046. https://doi.org/10.3390/curroncol31040150