KRAS: From undruggable to a druggable Cancer Target

Uprety, Dipesh; Adjei, Alex A.

doi:10.1016/j.ctrv.2020.102070

Cited by 175 publications

(140 citation statements)

References 178 publications

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“…Unlike sorafenib, v-RAF murine sarcoma viral oncogene homolog B1 (BRAF) inhibitors are RAF-specific inhibitors. Currently, many BRAF inhibitors, for instance, dabrafenib, vemurafenib, and encorafenib, have been approved to target BRAF V600 mutations, but RAF kinase inhibitors do not perform well in KRAS -mutant cells ( 48 , 49 ). ATP-competitive RAF inhibitors inhibit ERK signalling in mutant BRAF cells but enhance signal transduction in wild-type BRAF cells ( 50 ).…”

Section: Progress In Targeted Therapy For Kras-mutant Nsclcmentioning

confidence: 99%

KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup

Xie

Fan

2021

Front. Oncol.

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Lung cancer, the leading cause of cancer-related deaths worldwide, can be classified into small cell lung cancer and non-small cell lung cancer (NSCLC). NSCLC is the most common histological type, accounting for 85% of all lung cancers. Kirsten rat sarcoma viral oncogene (KRAS) mutations, common in NSCLC, are associated with poor prognosis, likely due to poor responses to most systemic therapies and lack of targeted drugs. The latest published clinical trial data on new small-molecule KRAS G12C inhibitors, AMG510 and MRTX849, indicate that these molecules may potentially help treat KRAS-mutant NSCLC. Simultaneously, within the immuno-therapeutic process, immune efficacy has been observed in those patients who have KRAS mutations. In this article, the pathogenesis, treatment status, progress of immunotherapy, and targeted therapy of KRAS-mutant NSCLC are reviewed.

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Section: Progress In Targeted Therapy For Kras-mutant Nsclcmentioning

confidence: 99%

KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup

Xie

Fan

2021

Front. Oncol.

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“…NRAS mutations are less frequent, appearing in about 7% of cases. Their role in carcinogenesis has been proven in the preclinical setting, and, despite not being usually sufficient to initiate cancer growth and progression, they contribute to the development and progression of both adenomas and adenocarcinomas [42] . KRAS mutation prevalence reaches 30% in lung adenocarcinomas and 5% in lung squamous cell carcinomas, and it has been shown to vary between 45%-54% in extrahepatic and 10%-15% in intrahepatic cholangiocarcinomas.…”

Section: Clinical Relevance and Prognostic/predictive Value Of Ras Gene Family Alterationsmentioning

confidence: 99%

“…In accordance with NCCN guidelines, testing may be carried out on histological or cytological samples from either the primitive lesion or a metastasis [60] . Available platforms range 85%-100% sensitivity and 98%-100% specificity [42] . RAS mutation is considered an early event in carcinogenesis, and consequently the mutational status is usually concordant between the primary tumor and metastatic lesions [61] .…”

Section: Ras In Metastatic Colorectal Cancermentioning

confidence: 99%

Research progress on KRAS mutations in colorectal cancer

Cefalì¹,

Epistolio²,

Palmarocchi³

et al. 2021

JCMT

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The RAS gene family, responsible for signal transduction within the mitogen activated protein kinase (MAPK) and phosphatidylinositol 3 kinase (PI3K) pathways, is frequently involved in carcinogenesis, and alterations in its member genes can be detected, with variable frequency, in a wide variety of solid and hematological cancers. These alterations may behave as prognostic-predictive biomarkers and driver mutations, making them an interesting therapeutic target. Since their discovery, many strategies have been pursued to act on their signaling pathways. Indeed, in clinical practice, KRAS, the most prominent member of the RAS gene family, represents an especially elusive target in most malignancies; pathway inhibition is carried out upstream, on the EGFR receptor, or downstream, most frequently on the BRAF/MEK/ERK cascade. Recently, clinically relevant direct RAS inhibition has been successfully achieved with the development of potent and selective covalent inhibitors of KRAS c.34G>T (p.G12C). These latest-generation drugs represent both a new and interesting tool in the therapeutic armamentarium and a symbolic end to the myth of KRAS undruggability. However, their clinical relevance and appropriate place in treatment strategies remain to be determined.

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“…Cumulatively, PYGL may involve the integration of signal transduction mechanisms through PI3K signaling to the activation of mTORC1 signaling. Moreover, it is well-accepted that KRAS is the most commonly mutated RAS oncogene isoform, and such mutation will constitutively activate thereby enhancing downstream signaling and leading to tumorigenesis (24). In the past, evidence-based observation suggested that interaction between mutated RAS cells and PI3K, and the maximal PI3K signaling is essential for the initiate tumor formation (25,26).…”

Section: Discussionmentioning

confidence: 99%

High PYGL Expression Predicts Poor Prognosis in Human Gliomas

Zhao

Hua

et al. 2021

Front. Neurol.

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Background: PYGL has been reported as a glycogen degradation-related gene, which is up-regulated in many tumors. This study was designed to investigate the predictive value of high PYGL expression in patients with gliomas through bioinformatics analysis of the gene transcriptome and the single-cell sequencing data.Methods: The gene transcriptome data of 595 glioma patients from the TCGA database and the single-cell RNA sequencing data of 7,930 GBM cells from the GEO database were included in the study. Differential analysis was used to find the distribution of expression of PYGL in different groups of glioma patients. OS analysis was used to assess the influence of the high expression of PYGL on the prognosis of patients. The reliability of its prediction was evaluated by the AUC of ROC and the C-index. The GSEA be used to reveal potential mechanisms. The single-cell analysis was used to observe the high expression of PYGL in different cell groups to further analyze the mechanism of its prediction.Results: Differential analysis identified the expression level of PYGL is positively associated with glioma malignancy. OS analysis and Cox regression analyses showed high expression of PYGL was an independent factor for poor prognosis of gliomas (p < 0.05). The AUC values were 0.838 (1-year ROC), 0.864 (3-year ROC) and 0.833 (5-year ROC). The C index was 0.81. The GSEA showed that gene sets related to MTORC1 signaling, glycolysis, hypoxia, PI3K/AKT/mTOR signaling, KRAS signaling up and angiogenesis were differentially enriched in the high PYGL expression phenotype. The single-cell sequencing data analysis showed TAMs and malignant cells in GBM tissues expressed a high level of PYGL.Conclusion: The high expression of PYGL is an independent predictor of poor prognosis in patients with glioma.

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KRAS: From undruggable to a druggable Cancer Target

Cited by 175 publications

References 178 publications

KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup

KRAS-Mutant Non-Small Cell Lung Cancer: An Emerging Promisingly Treatable Subgroup

Research progress on KRAS mutations in colorectal cancer

High PYGL Expression Predicts Poor Prognosis in Human Gliomas

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