The current state of the art and future trends in RAS-targeted cancer therapies

Punekar, Salman R; Velcheti, Vamsidhar; Neel, Benjamin G.; Wong, Kwok-Kin

doi:10.1038/s41571-022-00671-9

Cited by 250 publications

(182 citation statements)

References 209 publications

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“…The top three mutant genes in patients at high risk, including KRAS, TP53, and SMAD4. KRAS is the most frequently altered oncogene in sold tumors [33]. Its activating mutations occur in approximately 30% of all human cancers, including 90% of pancreatic cancers, 50% of colon cancers and 25% of lung cancers [34].…”

Section: Discussionmentioning

confidence: 99%

Construction of a cuproptosis-related lncRNA signature as a novel prognostic model for pancreatic adenocarcinoma

Zheng

et al. 2022

Preprint

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Background Pancreatic adenocarcinoma (PAAD) is one of the common malignant tumors, with high mortality and poor prognosis. Long non-coding RNA (lncRNA) plays a vital role in the progression of tumors. Cuproptosis, a newly identified form of programmed cell death, is thought to play a role in tumorigenesis. However, the role and prognostic value of cuproptosis-related lncRNA in PAAD remains unknown. Therefore, our study is to construct the role of cuproptosis-related lncRNA signature for predicting the prognosis of PAAD patients. Material and methods The mRNAs and lncRNAs expression profiles and clinical data of PAAD were obtained from The Cancer Genome Atlas (TCGA) databases. The prognosis signature was constructed by least absolute shrinkage and selection operator (LASSO) regression and Cox regression analysis. Patients were separated into high and low risk groups according to the median score. Using Kaplan-Meier, Concordance index (C-index), area under the receiver operating characteristic (ROC) curves to assess prognostic ability of the signature. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes Enrichment (KEGG), immune-related functions, and tumor mutation burden (TMB) were analyzed based on the signature. The likelihood of an immunotherapy response was estimated using tumor immune dysfunction and exclusion (TIDE) algorithms. PRRophetic package was used to identify its sensitivity toward potential drugs for PAAD. Results In total, we obtained 4 cuproptosis-related lncRNAs and constructed a prognostic signature. High-risk patients were correlated with worse overall survival (OS) and progression-free survival (PFS) and higher mortality. Multivariate Cox regression was performed to identify independent risk factor poor prognosis of high risk scores. ROC, C-index, and nomogram also showed the signature can accurately predict the prognosis of patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed the biological functions of lncRNAs are associated with tumor development, especially immune response. Tumor Mutation Burden (TMB) and Tumor Immune Dysfunction and Exclusion (TIDE) scores were significantly different between high- and low-risk groups. The three drugs, including Paclitaxel, Gefitinib, and 17-AAG, were more sensitive in the high-risk group. Conclusion The 4 cuproptosis-related lncRNAs signature accurately predicted the prognosis of PAAD and led to better prognosis and treatment options for patients.

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Section: Discussionmentioning

confidence: 99%

Construction of a cuproptosis-related lncRNA signature as a novel prognostic model for pancreatic adenocarcinoma

Zheng

et al. 2022

Preprint

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“…Nevertheless, because of the particularity of the KRAS protein structure, there is no effective drug to treat KRAS mutant tumours thus far. Epidermal growth factor receptor (EGFR) is the upstream signalling pathway of KRAS [ 144 , 145 ]. Through the study of targeted EGFR inhibitors, the upstream signalling pathway can be blocked to block the mutant expression of KRAS.…”

Section: Modulation Of Cell Death In Hnsccmentioning

confidence: 99%

Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma

et al. 2023

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Head and neck cancer is a malignant tumour with a high mortality rate characterized by late diagnosis, high recurrence and metastasis rates, and poor prognosis. Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck cancer. Various factors are involved in the occurrence and development of HNSCC, including external inflammatory stimuli and oncogenic viral infections. In recent years, studies on the regulation of cell death have provided new insights into the biology and therapeutic response of HNSCC, such as apoptosis, necroptosis, pyroptosis, autophagy, ferroptosis, and recently the newly discovered cuproptosis. We explored how various cell deaths act as a unique defence mechanism against cancer emergence and how they can be exploited to inhibit tumorigenesis and progression, thus introducing regulatory cell death (RCD) as a novel strategy for tumour therapy. In contrast to accidental cell death, RCD is controlled by specific signal transduction pathways, including TP53 signalling, KRAS signalling, NOTCH signalling, hypoxia signalling, and metabolic reprogramming. In this review, we describe the molecular mechanisms of nonapoptotic RCD and its relationship to HNSCC and discuss the crosstalk between relevant signalling pathways in HNSCC cells. We also highlight novel approaches to tumour elimination through RCD.

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“…RAS -mutant tumors are among the most aggressive and refractory to treatment ( Hymowitz and Malek, 2018 ; Punekar et al, 2022 ). Although some success in developing direct inhibitors of KRAS has been made recently ( Basso et al, 2006 ; Engelman et al, 2008 ; Cox et al, 2015 ; McCormick, 2015 ; Punekar et al, 2022 ), disappointing clinical trials of these agents ( Hu et al, 2000 ; Basso et al, 2006 ; Berndt et al, 2011 ; Riely et al, 2011 ; Gelderblom et al, 2020 ) (NCT01468688, NCT01297491, NCT03101839, NCT04111458) demonstrate that a multi-pronged approach will be required to have a significant therapeutic impact. The recent establishment of differential effects on metabolism of the two KRAS splice variants suggest the possibility of exploiting therapeutically unique metabolic vulnerabilities in cancers with relatively high expression of the KRAS4A.…”

Section: Kras Splice Variants and Glycolysismentioning

confidence: 99%

The role of KRAS splice variants in cancer biology

Nuevo‐Tapioles¹,

Philips²

2022

Front. Cell Dev. Biol.

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The three mammalian RAS genes (HRAS, NRAS and KRAS) encode four proteins that play central roles in cancer biology. Among them, KRAS is mutated more frequently in human cancer than any other oncogene. The pre-mRNA of KRAS is alternatively spliced to give rise to two products, KRAS4A and KRAS4B, which differ in the membrane targeting sequences at their respective C-termini. Notably, both KRAS4A and KRAS4B are oncogenic when KRAS is constitutively activated by mutation in exon 2 or 3. Whereas KRAS4B is the most studied oncoprotein, KRAS4A is understudied and until recently considered relatively unimportant. Emerging work has confirmed expression of KRAS4A in cancer and found non-overlapping functions of the splice variants. The most clearly demonstrated of these is direct regulation of hexokinase 1 by KRAS4A, suggesting that the metabolic vulnerabilities of KRAS-mutant tumors may be determined in part by the relative expression of the splice variants. The aim of this review is to address the most relevant characteristics and differential functions of the KRAS splice variants as they relate to cancer onset and progression.

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The current state of the art and future trends in RAS-targeted cancer therapies

Abstract: Table 1 | Selected KRAS-directed therapies Strategy and target Agent Phase of development Mutant-specific direct KRAS inhibitors KRAS G12C Sotorasib (AMG 510) Approved for previously treated advanced-stage KRAS G12C -mutant NSCLC; further clinical trials ongoing (NCT03600883,

Cited by 250 publications

References 209 publications

Construction of a cuproptosis-related lncRNA signature as a novel prognostic model for pancreatic adenocarcinoma

Construction of a cuproptosis-related lncRNA signature as a novel prognostic model for pancreatic adenocarcinoma

Effect of regulatory cell death on the occurrence and development of head and neck squamous cell carcinoma

The role of KRAS splice variants in cancer biology

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