The current understanding on the impact of KRAS on colorectal cancer

Meng, Mingjing; Zhong, Keying; Jiang, Ting; Liu, Zhongqiu; Kwan, Hiu Yee; Su, Tao

doi:10.1016/j.biopha.2021.111717

Cited by 85 publications

(61 citation statements)

References 146 publications

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“…The most common KRAS gene mutation is at glycine at G12, G13 and glutamine at Q61, while G12 has 15 different point mutations. These mutation leads to the aberrant activation of the signaling pathways including the RAF/MEK/MAPK pathway, PI3K/Akt pathway and RAGDS, RAL-RLIP pathways, leading to the malignant CRC progression and development [ 40 , 41 ]. Furthermore, KRAS mutation also influences the choice of surgical techniques and is an independent predictor for positive resection margins (HR 2.44, 95% CI 1.30–4.58, P = 0.005) [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Combination of artesunate and WNT974 induces KRAS protein degradation by upregulating E3 ligase ANACP2 and β-TrCP in the ubiquitin–proteasome pathway

et al. 2022

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Background KRAS mutation is one of the dominant gene mutations in colorectal cancer (CRC). Up to present, targeting KRAS for CRC treatment remains a clinical challenge. WNT974 (LGK974) is a porcupine inhibitor that interferes Wnt signaling pathway. Artesunate (ART) is a water-soluble semi-synthetic derivative of artemisinin. Methods The synergistic effect of ART and WNT974 combination in reducing CRC cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RT-PCR was utilized for the mRNA levels of KRAS, CUL7, ANAPC2, UBE2M, RNF123, SYVN1, or β-TrCP. Western blot assay was utilized for the protein levels of NRAS, HRAS, KRAS, ANAPC2, β-TrCP, GSK-3β, p-Akt (Ser473), t-Akt, p-PI3K (Tyr458), t-PI3K, p-mTOR (Ser2448), t-mTOR. Xenograft mouse model assay was performed for the anti-CRC effect of combination of ART and WNT974 in vivo. IHC assay was utilized for the levels of KRAS, β-TrCP, GSK-3β or ANAPC2 in tumor tissues. Results Our study shows that the combination of WNT974 and ART exhibits synergistic effect in reducing CRC growth. The combination treatment significantly reduces KRAS protein level and activity in CRC cells. Interestingly, the combination treatment increases E3 ligases ANAPC2 expression. Our data show that overexpression of ANAPC2 significantly reduces KRAS protein levels, which is reversed by MG132. Knockdown of ANAPC2 in CRC abolishes the combination treatment-reduce KRAS expression. Besides, the treatment also increases the expressions of GSK-3β and E3 ligase β-TrCP that is known to degrade GSK-3β-phosphorylated KRAS protein. Knockdown of β-TrCP- and inhibition of GSK-3β abolish the combination treatment-induce KRAS ubiquitination and reduction in expression. Last but not least, combination treatment suppresses PI3K/Akt/m-TOR signaling pathway. Conclusions Our data clearly show that the combination treatment significantly enhances KRAS protein degradation via the ubiquitination ubiquitin–proteasome pathway, which is also demonstrated in xenograft mouse model. The study provides strong scientific evidence for the development of the combination of WNT974 and ART as KRAS-targeting therapeutics for CRC treatment.

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Section: Discussionmentioning

confidence: 99%

Combination of artesunate and WNT974 induces KRAS protein degradation by upregulating E3 ligase ANACP2 and β-TrCP in the ubiquitin–proteasome pathway

et al. 2022

Self Cite

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show abstract

“…The most common KRAS gene mutation is at glycine at G12, G13 and glutamine at Q61, while G12 has 15 different point mutations. These mutation leads to the aberrant activation of the signaling pathways including the RAF/MEK/MAPK pathway, PI3K/AKT pathway and RAGDS, RAL-RLIP pathways, leading to the malignant CRC progression and development [40,41]. Furthermore, KRAS mutation also in uences the choice of surgical techniques and is an independent predictor for positive resection margins (HR 2.44, 95%, CI 1.30-4.58, P = 0.005) [42].…”

Section: Discussionmentioning

confidence: 99%

Combination of Artesunate and WNT974 Induces KRAS Protein Degradation by Upregulating E3 Ligase ANACP2 and β-TrCP in the Ubiquitin–proteasome Pathway

Gong¹,

Chen²,

Huang³

et al. 2021

Preprint

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BackgroundKRAS mutation is one of the dominant gene mutations in colorectal cancer (CRC). Up to present, targeting KRAS for CRC treatment remains a clinical challenge. WNT974 (LGK974) is a porcupine inhibitor that interferes Wnt signaling pathway. Artesunate (ART) is a water-soluble semi-synthetic derivative of artemisinin.MethodsThe synergistic effect of ART and WNT974 combination in reducing CRC cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RT-PCR was utilized for the mRNA levels of KRAS, CUL7, ANAPC2, UBE2M, RNF123, SYVN1, or β-TrCP. Western blot assay was utilized for the protein levels of KRAS, ANAPC2, β-TrCP, or GSK-3β. Xenograft mouse model assay was performed for the anti-CRC effect of combination of ART and WNT974 in vivo. IHC assay was utilized for the levels of KRAS, β-TrCP, or GSK-3β in tumor tissues.Results Our study shows that the combination of WNT974 and ART exhibits synergistic effect in reducing CRC growth. The combination treatment significantly reduces KRAS protein level and activity in CRC cells. Interestingly, the combination treatment increases E3 ligases ANAPC2 expression. Our data show that overexpression of ANAPC2 significantly reduces KRAS protein levels, which is reversed by MG132. Knockdown of ANAPC2 in CRC abolishes the combination treatment-reduce KRAS expression. Besides, the treatment also increases the expressions of GSK-3β and E3 ligase β-TrCP that is known to degrade GSK-3β-phosphorylated KRAS protein. Knockdown of β-TrCP- and inhibition of GSK-3β abolish the combination treatment-induce KRAS ubiquitination and reduction in expression.ConclusionsOur data clearly show that the combination treatment significantly enhances KRAS protein degradation via the ubiquitination ubiquitin–proteasome pathway, which is also demonstrated in xenograft mouse model. The study provides strong scientific evidence for the development of the combination of WNT974 and ART as KRAS-targeting therapeutics for CRC treatment.

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“…Different mutations of KRAS have shown tissue-specific incidences, such as G12V/C in lung cancer ( 47 , 48 ) and G12R in pancreatic cancer ( 49 ). Novel targeting therapies are currently being pursued as potential treatments for KRAS-mutant non-small-cell lung cancer ( 43 , 50 ) and KRAS-mutant colorectal cancer ( 51 , 52 ), which might be worthwhile for KRAS-mutant EC in the future.…”

Section: Kras Mutations In Ec and Its Potential Value In The Fertility-spared Treatmentmentioning

confidence: 99%

The Advance and Correlation of KRAS Mutation With the Fertility-Preservation Treatment of Endometrial Cancer in the Background of Molecular Classification Application

Yu¹,

Wang²

2021

Pathol. Oncol. Res.

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The annually increasing incidence of endometrial cancer in younger women has created a growing demand for fertility preservation. However, the diverse therapeutic efficacy among patients under the same histological subtype and the same tumor grade suggests the potential interference of the innate molecular characteristics. The molecular classification has now been applied in clinical practice and might help to stratify the endometrial cancer patients and individualize the therapy, but the candidates for the fertility-spared treatment are most likely to be subdivided in the subgroup lacking the specific signature. KRAS mutation has been linked to the malignant transition of the endometrium, while its role in molecular classification and fertility preservation is vague. Here, we mainly review the advance of molecular classification and the role of KRAS in endometrial cancer, as well as their correlation with fertility-preservation treatment.

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The current understanding on the impact of KRAS on colorectal cancer

Cited by 85 publications

References 146 publications

Combination of artesunate and WNT974 induces KRAS protein degradation by upregulating E3 ligase ANACP2 and β-TrCP in the ubiquitin–proteasome pathway

Combination of artesunate and WNT974 induces KRAS protein degradation by upregulating E3 ligase ANACP2 and β-TrCP in the ubiquitin–proteasome pathway

Combination of Artesunate and WNT974 Induces KRAS Protein Degradation by Upregulating E3 Ligase ANACP2 and β-TrCP in the Ubiquitin–proteasome Pathway

The Advance and Correlation of KRAS Mutation With the Fertility-Preservation Treatment of Endometrial Cancer in the Background of Molecular Classification Application

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