KRAS Cancer Research Results
KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog: Click to Expand ⟱
| Source: CGL-Driver Genes |
| Type: Oncogene |
KRAS (Kirsten rat sarcoma viral oncogene homolog) is a gene that encodes a protein involved in cell signaling pathways that control cell growth and division. Mutations in the KRAS gene are among the most common genetic alterations found in various types of cancer, particularly pancreatic, colorectal, and lung cancers.
Mutations in the KRAS gene lead to the production of a hyperactive KRAS protein.
Cancers with KRAS mutations are often more aggressive and associated with poorer prognosis.
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Scientific Papers found: Click to Expand⟱
Risk↓, Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval
other↝, However, some large cohorts found no association between aspirin use and CRC risk when aspirin was initiated after 70 years of age (9) and when aspirin was used for less than 10 years (10) or 20 years (11).
Dose↝, Use of 160 mg tablets was associated with a greater CRC risk reduction than the use of 75 mg tablets.
Risk↓, We found a 13% lower CRC risk associated with current low-dose aspirin use vs never use,
other↓, In 2020, a large meta-analysis of 15 cohort, 11 nested case-control, and 19 case-control studies reported a 27% reduced CRC risk in regular users of aspirin (7)
other↝, It was argued later that the limited follow-up time of participants without history of aspirin use before the trial enrollment could partly explain the negative results in the ASPREE trial (9,36).
KRAS↓, A mechanism supporting the hypothesis that aspirin has a protective effect against CRC risk is that aspirin blocks the mutated APC (adenomatous polyposis coli) gene, leading to the inhibition of the KRAS pathway and the adenomatous polyp formation (3
other↓, By assuming a protective effect of aspirin against CRC, we estimated that 1,073 cases with CRC were prevented by aspirin use, equating to 2.7% lower CRC incidence.
other↓, In conclusion, our study provided novel and strong evidence that low-dose aspirin use is associated with a lower CRC risk.
eff↑, Combining cetuximab with immunotherapy and other targeted agents further expands the therapeutic landscape, offering renewed hope for mCRC patients who face the development of resistance to conventional therapies.
Half-Life↑, Pharmacokinetic differences include cetuximab’s non-linear clearance and longer half-life, while panitumumab exhibits both linear and non-linear clearance mechanisms and a shorter half-life [23].
Half-Life↑, These studies revealed that clearance from the bloodstream was relatively slow, with a median half-life of 7 days
EGFR↓, Cetuximab also aids in downregulating EGFR-dependent signaling by promoting the internalization of EGFR
OS↑, Cetuximab improved OS and PFS compared with best supportive care (BSC), while maintaining quality of life [
QoL↑,
eff↑, The BEACON trial illustrated that the combination of BRAF inhibition and anti-EGFR therapy using cetuximab yielded better results compared with irinotecan-based chemotherapy in refractory BRAF V600E mCRC patients.
KRAS↓, nhibition of KRAS G12C and Cetuximab
Let-7↑,
KRAS↓,
Wnt↓, In particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK.
β-catenin/ZEB1↓,
RAS↓,
STAT3↓,
NOTCH↓,
E2Fs↓,
mTOR↓,
eff↑, Moreover, niclosamide potentially improves immunotherapy by modulating pathways such as PD-1/PDL-1.
PD-1↓,
PD-L1↓, primarily through PD-L1 ligand downregulation in cancer cells.
BioAv↝, The original pharmacokinetics study showed that the maximal serum concentration can reach 0.25-6.0ug/ml (0.76-18.34 µM) following administration of a single 2g dose (11).
toxicity↓, a strong safety profile and tolerability in humans.
BioAv↑, A potential solution to the aforementioned challenge is niclosamide ethanolamine (NEN), a salt form of niclosamide that also functions as a mitochondrial uncoupler with a superior safety profile and enhanced bioavailability
ETC↑, NEN activates the ETC to boost NADH oxidation, thereby leading to an increased intracellular NAD+/NADH ratio and driving the TCA cycle forward.
NADH:NAD↓,
TCA↑,
Warburg↓, leading to a reversal of the Warburg effect and the induction of cellular differentiation
Diff↑,
AMPK↑, figure 3
P53↑,
PP2A↑,
HIF-1↓,
KRAS↓,
Myc↓,
RadioS↑, leading to a reversal of the Warburg effect and the induction of cellular differentiation
ChemoSen↑, Niclosamide has shown synergistic anti-tumor effects with a broad spectrum of chemotherapy drugs.
Dose↝, In this trial, either 500mg or 1000mg niclosamide was given three times daily to patients. However, the maximal plasma concentration ranged from 35.7–82 ng/mL (0.1µM-0.25 µM), a range that failed to be consistently above the minimum effective concent
Dose↑, In contrast, the ongoing clinical trial NCT02807805 is administering 1200 mg of reformulated orally bioavailable niclosamide orally (PO) three times daily to patients, resulting in 0.21µM-0.723 plasma niclosamide concentrations exceeding the therape
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*antiOx↑, Quercetin has a potent antioxidant capacity, being able to capture reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive chlorine species (ROC),which act as reducing agents by chelating transition-metal ions.
*ROS↓, Quercetin is a potent scavenger of reactive oxygen species (ROS), protecting the organism against oxidative stress
*angioG↓,
*Inflam↓, anti-inflammatory properties; the ability to protect low-density lipoprotein (LDL) oxidation, and the ability to inhibit angiogenesis;
*BioAv↓, It is known that the bioavailability of quercetin is usually relatively low (0.17–7 μg/mL), less than 10% of what is consumed, due to its poor water solubility (hydrophobicity), chemical stability, and absorption profile.
*Half-Life↑, their slow elimination since their half-life ranges from 11 to 48 h, which could favor their accumulation in plasma after repeated intakes
*GSH↑, Animal and cell studies have demonstrated that quercetin induces the synthesis of GSH
*SOD↑, increase in the expression of superoxide dismutase (SOD), catalase (CAT), and GSH with quercetin pretreatment
*Catalase↑,
*Nrf1↑, quercetin accomplishes this process involves increasing the activity of the nuclear factor erythroid 2-related factor 2 (NRF2), enhancing its binding to the ARE, reducing its degradation
*BP↓, quercetin has been shown to inhibit ACE activity, reducing blood pressure
*cardioP↑, quercetin has positive effects on cardiovascular diseases
*IL10↓, Under the influence of quercetin, the levels of interleukin 10 (IL-10), IL-1β, and TNF-α were reduced.
*TNF-α↓,
*Aβ↓, quercetin’s ability to modulate the enzyme activity in clearing amyloid-beta (Aβ) plaques, a hallmark of AD pathology.
*GSK‐3β↓, quercetin can inhibit the activity of glycogen synthase kinase 3β,
*tau↓, thus reducing tau aggregation and neurofibrillary tangles in the brain
*neuroP↑,
*Pain↓, quercetin reduces pain and inflammation associated with arthritis
*COX2↓, quercetin included the inhibition of oxidative stress, production of cytokines such as cyclooxygenase-2 (COX-2) and proteoglycan degradation, and activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) (Nrf2/HO-1)
*NRF2↑,
*HO-1↑,
*IL1β↓, Mechanisms included decreased levels of TNF-α, IL-1β, IL-17, and monocyte chemoattractant protein-1 (MCP-1)
*IL17↓,
*MCP1↓,
PKCδ↓, studies with human leukemia 60 (HL-60) cells report that concentrations between 20 and 30 µM are sufficient to exert an inhibitory effect on cytosolic PKC activity and membrane tyrosine protein kinase (TPK) activity.
ERK↓, 50 µM resulted in the blockade of the extracellular signal-regulated kinases (ERK1/2) pathway
BAX↓, higher doses (75–100 µM) were used, as these doses reduced the expression of proapoptotic factors such as Bcl-2-associated X protein (Bax) and caspases 3 and 9
cMyc↓, induce apoptosis at concentrations of 80 µM and also causes a downregulation of cellular myelocytomatosis (c-myc) and Kirsten RAt sarcoma (K-ras) oncogenes
KRAS↓,
ROS↓, compound’s antioxidative effect changes entirely to a prooxidant effect at high concentrations, which induces selective cytotoxicity
selectivity↑, On the other hand, when noncancerous cells are exposed to quercetin, it exerts cytoprotective effects;
tumCV↓, decrease cell viability in human glioma cultures of the U-118 MG cell line as well as an increase in death by apoptosis and cell arrest at the G2 checkpoint of the cell cycle.
Apoptosis↑,
TumCCA↑,
eff↑, quercetin combined with doxorubicin can induce multinucleation of invasive tumor cells, downregulate P-glycoprotein (P-gp) expression, increase cell sensitivity to doxorubicin,
P-gp↓,
eff↑, resveratrol, quercetin, and catechin can effectively block the cell cycle and reduce cell proliferation in vivo
eff↑, cotreatment with epigallocatechin gallate (EGCG) inhibited catechol-O-methyltransferase (COMT) activity, decreasing COMT protein content and thereby arresting the cell cycle of PC-3 human prostate cancer cells
eff↑, synergistic treatment of tamoxifen and quercetin was also able to inhibit prostate tumor formation by regulating angiogenesis
eff↑, coadministration of 2.5 μM of EGCG, genistein, and quercetin suppressed the cell proliferation of a prostate cancer cell line (CWR22Rv1) by controlling androgen receptor and NAD (P)H: quinone oxidoreductase 1 (NQO1) expression
CycB/CCNB1↓, It can also downregulate cyclin B1 and cyclin-dependent kinase-1 (CDK-1),
CDK1↓,
CDK4↓, quercetin causes a decrease in cyclins D1/Cdk4 and E/Cdk2 and an increase in p21 in vascular smooth muscle cells
CDK2↓,
TOP2↓, quercetin is known to be a potent inhibitor of topoisomerase II (TopoII), a cell cycle-associated enzyme necessary for DNA replication
Cyt‑c↑, quercetin can induce apoptosis (cell death) through caspase-3 and caspase-9 activation, cytochrome c release, and poly ADP ribose polymerase (PARP) cleavage
cl‑PARP↑,
MMP↓, quercetin induces the loss of mitochondrial membrane potential, leading to the activation of the caspase cascade and cleavage of PARP.
HSP70/HSPA5↓, apoptotic effects of quercetin may result from the inhibition of HSP kinases, followed by the downregulation of HSP-70 and HSP-90 protein expression
HSP90↓,
MDM2↓, (MDM2), an onco-protein that promotes p53 destruction, can be inhibited by quercetin
RAS↓, quercetin can prevent Ras proteins from being expressed. In one study, quercetin was found to inhibit the expression of Harvey rat sarcoma (H-Ras), K-Ras, and neuroblastoma rat sarcoma (N-Ras) in human breast cancer cells,
eff↑, there was a substantial difference in EMT markers such as vimentin, N-cadherin, Snail, Slug, Twist, and E-cadherin protein expression in response to AuNPs-Qu-5, inhibiting the migration and invasion of MCF-7 and MDA-MB cells
Showing Research Papers: 1 to 5 of 5
* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5
Pathway results for Effect on Cancer / Diseased Cells:
Redox & Oxidative Stress ⓘ
ROS↓, 1,
Mitochondria & Bioenergetics ⓘ
ETC↑, 1, MMP↓, 1,
Core Metabolism/Glycolysis ⓘ
AMPK↑, 1, cMyc↓, 1, NADH:NAD↓, 1, TCA↑, 1, Warburg↓, 1,
Cell Death ⓘ
Apoptosis↑, 1, BAX↓, 1, Cyt‑c↑, 1, MDM2↓, 1, Myc↓, 1,
Transcription & Epigenetics ⓘ
other↓, 3, other↝, 2, tumCV↓, 1,
Protein Folding & ER Stress ⓘ
HSP70/HSPA5↓, 1, HSP90↓, 1,
DNA Damage & Repair ⓘ
P53↑, 1, cl‑PARP↑, 1,
Cell Cycle & Senescence ⓘ
CDK1↓, 1, CDK2↓, 1, CDK4↓, 1, CycB/CCNB1↓, 1, E2Fs↓, 1, TumCCA↑, 1,
Proliferation, Differentiation & Cell State ⓘ
Diff↑, 1, ERK↓, 1, Let-7↑, 1, mTOR↓, 1, NOTCH↓, 1, RAS↓, 2, STAT3↓, 1, TOP2↓, 1, Wnt↓, 1,
Migration ⓘ
KRAS↓, 5, PKCδ↓, 1, β-catenin/ZEB1↓, 1,
Angiogenesis & Vasculature ⓘ
EGFR↓, 1, HIF-1↓, 1,
Barriers & Transport ⓘ
P-gp↓, 1,
Immune & Inflammatory Signaling ⓘ
PD-1↓, 1, PD-L1↓, 1,
Protein Aggregation ⓘ
PP2A↑, 1,
Drug Metabolism & Resistance ⓘ
BioAv↑, 1, BioAv↝, 1, ChemoSen↑, 1, Dose↑, 1, Dose↝, 2, eff↑, 9, Half-Life↑, 2, RadioS↑, 1, selectivity↑, 1,
Clinical Biomarkers ⓘ
EGFR↓, 1, KRAS↓, 5, Myc↓, 1, PD-L1↓, 1,
Functional Outcomes ⓘ
OS↑, 1, QoL↑, 1, Risk↓, 2, toxicity↓, 1,
Total Targets: 61
Pathway results for Effect on Normal Cells:
Redox & Oxidative Stress ⓘ
antiOx↑, 1, Catalase↑, 1, GSH↑, 1, HO-1↑, 1, Nrf1↑, 1, NRF2↑, 1, ROS↓, 1, SOD↑, 1,
Proliferation, Differentiation & Cell State ⓘ
GSK‐3β↓, 1,
Angiogenesis & Vasculature ⓘ
angioG↓, 1,
Immune & Inflammatory Signaling ⓘ
COX2↓, 1, IL10↓, 1, IL17↓, 1, IL1β↓, 1, Inflam↓, 1, MCP1↓, 1, TNF-α↓, 1,
Synaptic & Neurotransmission ⓘ
tau↓, 1,
Protein Aggregation ⓘ
Aβ↓, 1,
Drug Metabolism & Resistance ⓘ
BioAv↓, 1, Half-Life↑, 1,
Clinical Biomarkers ⓘ
BP↓, 1,
Functional Outcomes ⓘ
cardioP↑, 1, neuroP↑, 1, Pain↓, 1,
Total Targets: 25
Scientific Paper Hit Count for: KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
Query results interpretion may depend on "conditions" listed in the research papers.
Such Conditions may include :
-low or high Dose
-format for product, such as nano of lipid formations
-different cell line effects
-synergies with other products
-if effect was for normal or cancerous cells
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