Key points
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KRAS is the most frequently mutated oncogene in human cancer and has challenged the development of clinical anticancer therapeutics in the last 30 years.
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Mutated KRAS oncoprotein disrupts GAP-mediated GTP hydrolysis and thus remains in a continuous GTP binding activation state.
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Small-molecule inhibitors that directly target KRAS-G12C mutants provide new tools for precision oncology.
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Clinical trials involving covalent KRAS-G12C inhibitors (adagrasib and sotorasib) have shown promising activity against lung cancers harboring KRAS-G12C mutations.
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Secondary KRAS mutations, gain-of-function mutations of the MAPK pathway, loss-of-function mutations in tumor suppressor genes, and other gene alterations are conducive to acquired resistance to KRAS-G12C inhibitors.
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The design and implementation of strategies to minimize or overcome drug resistance is an important goal for the further development of KRAS inhibitors.
Introduction
Target | Agent | Combinations | Study phase | Tumor type | Recruitment status | Trial number |
---|---|---|---|---|---|---|
BRAF, CRAF | LXH-254 | None | I | Advanced solid tumors harboring MAPK pathway alterations | Active, not recruiting | NCT02607813 |
BRAF, CRAF | LXH-254 | Rineterkib (RAF/ERK inhibitor); trametinib (MEK inhibitor); ribociclib (CDK4/6 inhibitor); EGF816 (EGFR inhibitor); dabrafenib (BRAF mutant inhibitor) | I, II | Unresectable or metastatic melanoma; EGFR-mutant NSCLC | Recruiting; active, not recruiting | NCT04417621; NCT02974725; NCT03333343; NCT04294160 |
ERK | LY3214996; GDC-0994; ulixertinib; MK-8353 | None | I, II | Acute myeloid leukemia; locally advanced or metastatic solid tumors; metastatic uveal melanoma; acute myelogenous leukemia or myelodysplastic syndromes | Recruiting; completed; terminated | NCT04081259; NCT01875705; NCT04488003; NCT03417739; NCT02296242; NCT01358331 |
ERK | LY3214996 | RMC-4630 (SHP2-inhibitor); abemaciclib (CDK4/6 inhibitor); hydroxychloroquine (autophagy inhibitor) | I, II | Metastatic KRAS mutant cancers; solid tumors harboring pathogenic alterations in BRAF, RAF1, MEK1/2, ERK1/2, and NF1 | Not yet recruiting | NCT04916236; NCT04956640; NCT04534283; NCT04616183; NCT04391595; NCT04386057 |
ERK | GDC-0994 | Cobimetinib (MEK inhibitor) | I | Locally advanced or metastatic solid tumors | Completed | NCT02457793 |
ERK | Ulixertinib | Hydroxychloroquine (autophagy inhibitor); palbociclib (CDK4/6 inhibitor) | I, II | Advanced MAPK-mutated gastrointestinal adenocarcinomas; advanced pancreatic and other solid tumors | Recruiting | NCT041452973; NCT03454035 |
ERK | MK-8353 | Selumetinib (MEK inhibitor); pembrolizumab (anti–PD-1 ab) | I | Advanced malignancies | Completed; active, not recruiting | NCT03745989; NCT02972034 |
KRAS | AZD4785 | None | I | Advanced solid tumors | Completed | NCT03101839 |
KRAS-G12C | Sotorasib | None | I, II | KRAS-G12C–mutant advanced/metastatic solid tumors | Recruiting; not yet recruiting | NCT04380753; NCT04625647; NCT04667234; NCT04933695 |
KRAS-G12C | Sotorasib | Docetaxel (microtubule inhibitor); pembrolizumab (anti–PD-1 ab) | I, II, III | KRAS-G12C–mutant advanced/metastatic solid tumors | Active, not recruiting; recruiting | NCT04303780; NCT03600883; NCT04613596 |
KRAS-G12C | Adagrasib | Docetaxel (microtubule inhibitor); pembrolizumab (anti–PD-1 ab); cetuximab (anti-EGFR ab); afatinib (pan-EGFR inhibitor); TNO155 (SHP2 inhibitor) | I, II, III | KRAS-G12C–mutant advanced/metastatic solid tumors | Recruiting | NCT04685135; NCT03785249; NCT04330664; NCT04793958 |
KRAS-G12C | GDC-6036 | Atezolizumab (anti–PD-L1 ab); cetuximab (anti-EGFR ab); bevacizumab (anti-VEGF ab); erlotinib (EGFR inhibitor) | I | KRAS-G12C–mutant advanced/metastatic solid tumors | Recruiting | NCT04449874 |
KRAS-G12C | D-1553 | Standard treatment | I | KRAS-G12C–mutant advanced/metastatic solid tumors | Recruiting | NCT04585035 |
KRAS-G12C | JNJ-74699157 | Standard treatment | I | KRAS-G12C–mutant advanced/metastatic solid tumors | Completed | NCT04006301 |
KRAS-G12C | LY3499446 | Abemaciclib (CDK4/6 inhibitor); cetuximab (anti-EGFR ab); erlotinib (EGFR inhibitor); docetaxel (microtubule inhibitor) | I, II | KRAS-G12C–mutant advanced/metastatic solid tumors | Terminated | NCT04165031 |
KRAS-G12D | siG12D-LODER | Gemcitabine + nab-paclitaxel; FOLFIRINOX | II | Advanced pancreatic cancer | Recruiting | NCT01676259 |
MEK | Cobimetinib | Belvarafenib (RAF inhibitor) | I | Advanced or metastatic solid tumors | Recruiting | NCT03284502 |
MEK | Trametinib | LXH254 (RAF inhibitor) | I | NSCLC or melanoma | Recruiting | NCT02974725 |
MEK | Pimasertib | None | I | N-RAS–mutated locally advanced or metastasis malignant cutaneous melanoma | Recruiting | NCT01693068, NCT00982865 |
MEK | Pimasertib | SAR405838 (MDM2 antagonist) | I | Advanced solid tumors | Completed | NCT01985191 |
MEK | Mirdametinib | Lifirfenib | I | Advanced or refractory solid tumors | Recruiting | NCT03905148 |
p110α | Alpelisib | Capecitabine (nucleoside metabolic inhibitor); paclitaxel (microtubule inhibitor) | I | Patients with PIK3CA mutant metastatic colorectal cancer; PIK3CA-altered metastatic/recurrent gastric cancer | Not yet recruiting | NCT04753203; NCT04526470 |
p110α | GDC-0077 | Entrectinib (pan-TRK inhibitor) | I | Breast cancer and advanced solid tumors | Recruiting | NCT04632992 |
RAF | PLX8394; TAK-580 | None | I, II | Advanced unresectable solid tumors; low-grade glioma | Recruiting | NCT02428712; NCT03429803 |
RAF | Belvarafenib | None | I | Solid tumors | Completed | NCT02405065 |
RAF | Belvarafenib | Cobimetinib (MEK inhibitor); cetuximab (anti-EGFR ab); atezolizumab (anti–PD-L1 ab) | I | Advanced or metastatic solid tumors; NRAS-mutant advanced melanoma | Recruiting | NCT03284502; NCT04835805 |
RAF, EGFR | Lifirfenib | None | I | Solid tumors | Completed | NCT02610361; NCT03641586 |
RAF, EGFR | Lifirfenib | Mirdametinib (MEK inhibitor) | I | NSCLC with confirmed KRAS mutations | Recruiting | NCT04294160 |
SHP2 | BBP-398; JAB-3068; RMC-4630; RLY-1971; JAB-3312; SH3809 | None | I, II | Advanced or metastatic solid tumors | Recruiting | NCT04528836; NCT03565003; NCT03518554; NCT03634982; NCT04252339; NCT04121286; NCT04045496; NCT04843033 |
SHP2 | RMC-4630 | LY3214996 (ERK inhibitor); cobimetinib (MEK inhibitor); osimertinib (EGFR inhibitor) | I, II | Advanced or metastatic solid tumors | Not yet recruiting; recruiting | NCT04916236; NCT03989115 |
SHP2 | ERAS-601 | Cobimetinib (MEK inhibitor) | I | Advanced or metastatic solid tumors | Recruiting | NCT04670679 |
SHP2 | TNO155 | Nazartinib (EGFR inhibitor); spartalizumab (anti–IL-1β antibody); ribociclib (CDK4/6 inhibitor); adagrasib (KRAS-G12C inhibitor); JDQ443 (KRAS-G12C inhibitor) | I, II | Advanced solid tumors | Recruiting | NCT03114319; NCT04000529; NCT04330664; NCT04699188 |
SOS1 | BI 1701963 | Trametinib (MEK inhibitor); BI 3011441 (MEK inhibitor); irinotecan (topoisomerase I inhibitor) | I | Advanced or metastatic solid tumors | Recruiting | NCT04111458; NCT04835714; NCT04627142 |
Type and frequency of KRAS mutation
Prognostic and predictive value of KRAS mutations
Tyrosine kinase inhibitors (TKIs) are a group of drugs that disrupt the tyrosine kinase (TK) signal transduction pathway through a variety of mechanisms. They can compete with adenosine triphosphate (ATP), phosphorylated entities, substrates, or can act in an allosteric manner, that is, bind to sites outside the active site and affect the sites’ activity through conformational changes. TKs can be divided into receptor tyrosine kinases (RTKs), nonreceptor tyrosine kinases (NRTKs), and dual-specific kinases (DSKs). DSKs phosphorylate serine, threonine, and tyrosine residues. Approximately 20 different transmembrane RTK subfamilies have been identified, such the families for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), insulin receptor (INSR), fibroblast growth factor receptor (FGFR), and epidermal growth factor receptor (EGFR). NRTKs are cytoplasmic proteins and do not have a transmembrane domain. NRTKs are mainly composed of nine families, including those for Abl, Ack, Csk, Fak, Fes/Fer, Jak, Src, Syk/Zap70, and Tec. The most typical example of DSK is mitogen-activated protein kinase kinase (MEK), which is involved in the mitogen-activated protein kinase (MAPK) pathway. More than 50 FDA-approved TKIs (including small-molecule inhibitors and monoclonal antibodies) are used to treat various diseases, including cancer. |
Immune checkpoint inhibitors (ICIs) are a group of drugs that inhibit the activity and function of inhibitory immune checkpoint molecules, such as programmed cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG3), and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3). Under physiological conditions, inhibitory immune checkpoint molecules play an important role in maintaining self-tolerance, preventing autoimmune reactions, and minimizing tissue damage by regulating the duration and intensity of immune responses. However, abnormal expression and excessive activation of immune checkpoint molecules can cause many diseases, including cancer. In particular, inhibitory immune checkpoint molecules are upregulated in various cells within the tumor microenvironment, forming various pairings and limiting the normal antitumor function of immune cells. In contrast, the use of ICIs can restore the function of immune cells hijacked by cancer cells, resulting in an enhanced immunosurveillance with a cytotoxic T lymphocyte (CTL) response. ICIs (e.g., pembrolizumab, nivolumab, cemiplimab, and atezolizumab) have changed the landscape of cancer treatment and become a new hope for cancer patients after the failure of regular chemotherapy or radiotherapy. |
Activation and modulation of KRAS mutations
Indirect KRAS suppression strategies
Inhibition of KRAS expression
Inhibition of KRAS processing
Inhibition of upstream signaling molecules
Inhibition of downstream signaling molecules
RAF inhibitors
MEK inhibitors
ERK inhibitors
PI3K pathway inhibitors
Others
Synthetic lethal genes | Full name | Main function | Tumor type | Reference |
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ANAPC1 | Anaphase-promoting complex subunit 1 | Mediates cell cycle progression | KRAS-mutant colon cancer | [147] |
ARHGEF2 | Rho/Rac guanine nucleotide exchange factor 2 | Activates Rho-GTPases | KRAS-mutant pancreatic cancer | [148] |
BCL2L1 (BCL-XL) | BCL2-like 1 | Inhibits apoptosis | KRAS-mutant solid cancer | [149] |
BIRC5 (survivin) | Baculoviral IAP repeat containing 5 | Inhibits apoptosis | KRAS-mutant colon cancer | [150] |
CDK1 | Cyclin-dependent kinase 1 | Mediates cell cycle progression | KRAS-mutant colon cancer | [151] |
CDK4 | Cyclin-dependent kinase 4 | Mediates cell cycle progression | KRAS-mutant lung cancer | |
DHODH | Dihydroorotate dehydrogenase (quinone) | Inhibits mitochondrial oxidative damage | KRAS-mutant pancreatic cancer | [154] |
FGFR1 | Fibroblast growth factor receptor 1 | Mediates mitogenesis and differentiation | KRAS-mutant lung cancer | [155] |
GATA2 | GATA binding protein 2 | Promotes development and survival | KRAS-mutant lung cancer | [156] |
MAP3K7 (TAK1) | Mitogen-activated protein kinase kinase kinase 7 | Promotes NF-κB activation | KRAS-mutant colon cancer | [157] |
PLK1 | Polo-like kinase 1 | Promotes centrosome maturation and spindle assembly | KRAS-mutant chronic myelomonocytic leukemia or solid cancer | |
PRMT5 | Protein arginine methyltransferase 5 | Arginine methyltransferase | KRAS-mutant pancreatic cancer | [160] |
PSMA5 | Proteasome 20S subunit alpha 5 | Mediates protein degradation | KRAS-mutant colon cancer | [147] |
SHOC2 | SHOC2 leucine-rich repeat scaffold protein | Promotes RAS signaling | KRAS-mutant leukemia and solid cancer | |
SHP2 (PTPN11) | SH2 containing protein tyrosine phosphatase 2 | Promotes RAS signaling | KRAS-mutant solid cancer | |
SNAI2 | Snail family transcriptional repressor 2 | Promotes epithelial-mesenchymal transition | KRAS-mutant colon cancer | [164] |
STK33 | Serine/threonine kinase 33 | Regulates cell cytoskeleton | KRAS-mutant solid cancer | [165] |
TBK1 | TANK binding kinase 1 | Promotes NF-κB activation | KRAS-mutant lung cancer | [166] |
WT1 | WT1 transcription factor | Promotes development and survival | KRAS-mutant lung cancer | [167] |
XPO1 | Exportin 1 | Mediates nuclear export | KRAS-mutant lung cancer | [168] |
YAP1 | Yes1-associated transcriptional regulator | Mediates the Hippo signaling pathway | KRAS-mutant pancreatic cancer | [167] |
Direct KRAS inhibition
Covalent KRAS-G12C inhibitors
Name | Application date | Institutions | Structure | Status | Reference/ trial number |
---|---|---|---|---|---|
1_AM | August 2017 | Dana-Farber Cancer Institute | Preclinical | [169] | |
Adagrasib | October 2019 | Mirati | Clinical (approved) | [16] NCT04685135; NCT03785249; NCT04330664; NCT04793958 | |
ARS-853 | January 2016 | Memorial Sloan Kettering Cancer Center | Preclinical | [170] | |
ARS-1620 | January 2018 | Wellspring Biosciences | Preclinical | [171] | |
Compound 12 | November 2013 | University of California | Preclinical | [172] | |
D-1553 | October 2020 | InventisBio | Structure not disclosed | Clinical (recruiting) | NCT04585035 |
GDC-6036 | June 2020 | Genentech | Structure not disclosed | Clinical (recruiting) | NCT04449874 |
JNJ-74699157 | July 2019 | Araxes/J&J | Structure not disclosed | Clinical (terminated) | NCT04006301 |
LY3499446 | November 2019 | Eli Lilly | Structure not disclosed | Clinical (terminated) | NCT04165031 |
Sotorasib | October 2019 | Amgen | Clinical (approved) | [15] NCT04303780; NCT03600883; NCT04613596 |
Hong et al., 2020 (n = 129) [177] | Skoulidis et al., 2021 (n = 126) [178] | |
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Characteristics | ||
Median age (range, year) | 62 (33–83) | 63.5 (37–80) |
NSCLC (n) | 59 | 126 |
CRC (n) | 42 | 0 |
Other solid cancer (n) | 28 | 0 |
Treatment | Sotorasib (orally 180-960 mg/kg, once daily) | Sotorasib (orally 960 mg/kg, once daily) |
Efficacy | ||
Objective response (%) | NSCLC: 32.2; CRC: 7.1; Other: 14.3 | 37.1 |
Disease control (%) | NSCLC: 88.1; CRC: 73.8; Other: 75.0 | 80.6 |
Complete response (%) | NSCLC: 0; CRC: 0; Other: 0 | 3.2 |
Partial response (%) | NSCLC: 32.2; CRC: 7.1; Other: 14.3 | 33.9 |
Stable disease (%) | NSCLC: 55.9; CRC: 66.7; Other: 60.7 | 43.5 |
Progressive disease (%) | NSCLC: 8.5; CRC: 23.8; Other: 14.3 | 16.1 |
Could not be evaluated (%) | NSCLC: 1.7; CRC: 2.4; Other: 7.1 | 1.6 |
Adverse events | ||
Any grade (%) | 96.9 | 99.2 |
Serious (%) | 45.0 | 45.3 |
Resulting in discontinuation of treatment (%) | 7.0 | 7.1 |