RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression

Sanclemente, Manuel; Nieto, Patricia; García-Alonso, Sara; Fernández-García, Fernando; Esteban-Burgos, Laura; Guerra, Carmen; Drosten, Matthias; Caleiras, Eduardo; Martı́nez-Torrecuadrada, Jorge L.; Santamarı́a, David; Musteanu, Mónica; Barbacid, Mariano

doi:10.1016/j.ccell.2021.01.008

Cited by 21 publications

(25 citation statements)

References 10 publications

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“…Interestingly, loss of RAF1 expression impaired tumour formation by stimulating apoptosis that is not dependent on ERK activity suggesting that it is the loss of RAF1 mediated MST2 and ASK1 inhibition that triggers apoptosis and restrains tumour growth. In support of this conclusion, the conditional expression of the kinase dead RAF1 D468A and RAF1 K375M mutants from the endogenous locus had limited impact on the formation of lung tumours in the KRAS G12V /p53 -/-mice [47]. These results clearly showed that the inhibitory effect of RAF1 on mutant KRAS driven lung tumour progression is due to kinase independent functions of RAF1.…”

Section: Raf Kinase Independent Functions and Kras Mediated Cancer: Omentioning

confidence: 60%

“…Importantly, work from Zhou's group showed that NF2 (Neurofibromatosis 2), a member of the canonical hippo pathway, regulates the interaction between MST1/2 and RAF1 in mice liver downstream of FGFR4 (Fibroblast growth factor receptor 4) to regulate organ size, which is one of the best-known functions of the canonical Hippo pathway [46]. Finally, recent work from Barbacid's group that will be discussed below shows that MST2 is one of the key mediators of the apoptosis caused by RAF1 ablation in murine KRAS/p53 mutant lung tumours [47]. The emerging picture firmly places the RAF1-MST1/2 complex as a hub that coordinates apoptotic with developmental and oncogenic signalling.…”

Section: Mammalian Ste20-like Kinase 2 (Mst2) and The Pro-apoptotic Hmentioning

confidence: 99%

“…However, it will be equally important to assess how such inhibitors impact on the kinase independent functions of RAF1 due to allosteric changes in protein conformation that could influence binding to ASK1 or MST2. This is emphasized by recent results from the Barbacid's group [47]. These works have focussed on the effect that RAF1 ablation has in the development of murine lung adenocarcinomas induced by KRAS and p53 mutations.…”

Section: Raf Kinase Independent Functions and Kras Mediated Cancer: Omentioning

confidence: 99%

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Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

Nolan

Aboud

Kölch

et al. 2021

Preprint

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Oncogenic RAS mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. So far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase independent functions in apoptosis, cell cycle progression and cell migration.

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Section: Raf Kinase Independent Functions and Kras Mediated Cancer: Omentioning

confidence: 60%

Section: Mammalian Ste20-like Kinase 2 (Mst2) and The Pro-apoptotic Hmentioning

confidence: 99%

Section: Raf Kinase Independent Functions and Kras Mediated Cancer: Omentioning

confidence: 99%

See 1 more Smart Citation

Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

Nolan

Aboud

Kölch

et al. 2021

Preprint

View full text Add to dashboard Cite

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“…The previous study did not explore the causes of poor survival and prognosis in the high-risk group. In our study, the relationship with immune infiltration was found in the high-risk group to be mainly enriched in genes upregulated in response to hypoxia [ 50 – 52 ], TNF [ 53 , 54 ], EMT [ 55 , 56 ], wound healing, fibrosis, metastasis, and KRAS activation [ 57 , 58 ]. These pathways are closely related to tumorigenesis, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Autophagy-Related Gene Nomograms to Predict the Prognostic Value of Patients with Cervical Cancer

Jiang

Wang

et al. 2021

Journal of Oncology

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Autophagy is a process of engulfing one’s own cytoplasmic proteins or organelles and coating them into vesicles, fusing with lysosomes to form autophagic lysosomes, and degrading the contents it encapsulates. Increasing studies have shown that autophagy disorders are closely related to the occurrence of tumors. However, the prognostic role of autophagy genes in cervical cancer is still unclear. In this study, we constructed risk signatures of autophagy-related genes (ARGs) to predict the prognosis of cervical cancer. The expression profiles and clinical information of autophagy gene sets were downloaded from TCGA and GSE52903 queues as training and validation sets. The normal cervical tissue expression profile data from the UCSC XENA website (obtained from GTEx) were used as a supplement to the TCGA normal cervical tissue. Univariate COX regression analysis of 17 different autophagy genes was performed with the consensus approach. Tumor samples from TCGA were divided into six subtypes, and the clinical traits of the six subtypes had different distributions. Further absolute shrinkage and selection operator (LASSO) and multivariable COX regression yielded an autophagy genetic risk model consisting of eight genes. In the training set, the survival rate of the high-risk group was lower than that of the low-risk group ( p < 0.0001). In the validation set, the AUC area of the receiver operating characteristic (ROC) curve was 0.772 for the training set and 0.889 for the verification set. We found that high and low risk scores were closely related to TNM stage ( p < 0.05). The nomogram shows that the risk score combined with other indicators, such as G, T, M, and N, better predicts 1-, 3-, and 5-year survival rates. Decline curve analysis (DCA) shows that the risk model combined with other indicators produces better clinical efficacy. Immune cells with an enrichment score of 28 showed statistically significant differences related to high and low risk. GSEA enrichment analysis showed the main enrichment being in KRAS activation, genes defining epithelial and mesenchymal transition (EMT), raised in response to the low oxygen level (hypoxia) gene and NF-kB in response to TNF. These pathways are closely related to the occurrence of tumors. Our constructed autophagy risk signature may be a prognostic tool for cervical cancer.

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“…Importantly, work from Zhou's group showed that NF2 (Neurofibromatosis 2), a member of the canonical hippo pathway, regulates the interaction between MST1/2 and RAF1 in mice liver downstream of FGFR4 (Fibroblast growth factor receptor 4) to regulate organ size, which is one of the best-known functions of the canonical Hippo pathway [49]. Finally, recent work from Barbacid's group that will be discussed below shows that MST2 is one of the key mediators of the apoptosis caused by RAF1 ablation in murine KRAS/p53 mutant lung tumours [50]. The emerging picture firmly places the RAF1-MST1/2 complex as a hub that coordinates apoptotic with developmental and oncogenic signalling.…”

Section: Mammalian Ste20-like Kinase 2 (Mst2) and The Proapoptotic Hippo Pathwaymentioning

confidence: 99%

Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

Nolan

Aboud

Kölch

et al. 2021

Genes

View full text Add to dashboard Cite

Oncogenic RAS (Rat sarcoma) mutations drive more than half of human cancers, and RAS inhibition is the holy grail of oncology. Thirty years of relentless efforts and harsh disappointments have taught us about the intricacies of oncogenic RAS signalling that allow us to now get a pharmacological grip on this elusive protein. The inhibition of effector pathways, such as the RAF-MEK-ERK pathway, has largely proven disappointing. Thus far, most of these efforts were aimed at blocking the activation of ERK. Here, we discuss RAF-dependent pathways that are regulated through RAF functions independent of catalytic activity and their potential role as targets to block oncogenic RAS signalling. We focus on the now well documented roles of RAF kinase-independent functions in apoptosis, cell cycle progression and cell migration.

show abstract

RAF1 kinase activity is dispensable for KRAS/p53 mutant lung tumor progression

Cited by 21 publications

References 10 publications

Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

Identification and Validation of Autophagy-Related Gene Nomograms to Predict the Prognostic Value of Patients with Cervical Cancer

Hidden Targets in RAF Signalling Pathways to Block Oncogenic RAS Signalling

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