Emerging RAS-directed therapies for cancer

Conroy, Michael; Cowzer, Darren; Kölch, Walter; Duffy, Austin G.

doi:10.20517/cdr.2021.07

Cited by 10 publications

(9 citation statements)

References 94 publications

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“…52 Despite the enormous studies conducted, RAS, however, stood apart; it is allegedly termed "undruggable" and direct RAS inhibitor development proved exceedingly challenging. 53 Direct drugging of RAS protein was considered paradoxical due to the absence of a drug-binding pocket; consequently, studies started focusing on the proteins upstream and downstream of RAS that could help suppress the oncogenic signal. 41 Albeit drugging RAS had initial failures, tremendous efforts in understanding the complications of RAS have initiated new avenues for next-generation anti-RAS drug discovery by NCI (National Cancer Institute).…”

Section: Ras Signaling Pathwaymentioning

confidence: 99%

Role of RAS signaling in ovarian cancer

et al. 2022

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The RAS family of proteins is among the most frequently mutated genes in human malignancies. In ovarian cancer (OC), the most lethal gynecological malignancy, RAS, especially KRAS mutational status at codons 12, 13, and 61, ranges from 6–65% spanning different histo-types. Normally RAS regulates several signaling pathways involved in a myriad of cellular signaling cascades mediating numerous cellular processes like cell proliferation, differentiation, invasion, and death. Aberrant activation of RAS leads to uncontrolled induction of several downstream signaling pathways such as RAF-1/MAPK (mitogen-activated protein kinase), PI3K phosphoinositide-3 kinase (PI3K)/AKT, RalGEFs, Rac/Rho, BRAF (v-Raf murine sarcoma viral oncogene homolog B), MEK1 (mitogen-activated protein kinase kinase 1), ERK (extracellular signal-regulated kinase), PKB (protein kinase B) and PKC (protein kinase C) involved in cell proliferation as well as maintenance pathways thereby driving tumorigenesis and cancer cell propagation. KRAS mutation is also known to be a biomarker for poor outcome and chemoresistance in OC. As a malignancy with several histotypes showing varying histopathological characteristics, we focus on reviewing recent literature showcasing the involvement of oncogenic RAS in mediating carcinogenesis and chemoresistance in OC and its subtypes.

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Section: Ras Signaling Pathwaymentioning

confidence: 99%

Role of RAS signaling in ovarian cancer

et al. 2022

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“…To further determine the method's feasibility, these chemical modifications on wider ranges of proteins via the lysine-based ligation have been conveyed (SI Figures S3−16). Specifically, lysozyme, myoglobin, RNase A, HRAS, KRAS, 29 as well as MiaA (tRNA dimethylallyl transferase) 30 were intensively evaluated. The Western blotting assays indicated that the treatment with chemical reagents (1-NO pyrene, 2t, 50 μM or 100 μM) led to a minimal effect on those proteins when staining with GoldView, although the in-gel blue fluorescence varied for each of those proteins.…”

Section: Explorations Of the Reaction On Proteinsmentioning

confidence: 99%

Deciphering Regulatory Proteins of Prenylated Protein via the FRET Technique Using Nitroso-Based Ene-Ligation and Sequential Azidation and Click Reaction

Gan

Zhou

et al. 2022

Org. Lett.

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We report here the selective incorporations of nitroso species into a wide range of proteins targeting lysine residue(s). The corresponding azo functionalities were formed in a highly selective manner with excellent yields, displaying rather good stability under physiological conditions. Furthermore, the azodation proceeded smoothly in high yields on targeted peptides. Fluorescent and/or dual fluorescent labeling of varied proteins following this protocol have been determined efficiently and selectively. With this established protocol, we aim to determine its usage in the evaluation of the interaction of prenylated proteins with their interacted enzyme(s) via FRET assays. Delightedly, chemically modified proteins with a 1-pyrenyl fluorophore through 254 nm UV irradiation and the sequential azodation and click reaction of protein prenyl functionality, which enable the incorporation of naphthene, indeed increase the fluorescence energy transferred since we observed significantly enhanced absorption located at 218 nm in lysed HEK293T cells and a clearly strengthened greenish fluorescence in living HEK293T cells.

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“…Based on this mechanism, bisphosphonates are mainly prescribed in patients with Paget disease of the bone, osteoporosis, myelomas and bone metastases [ 94 ]. Farnesyltransferase inhibitors (e.g., lonafarnib, tipifarnib) were developed as anti-cancer agents to specifically disrupt Ras farnesylation [ 96 ]. Geranylgeranyl transferase inhibitors (e.g., GGTI-2148, GGTI-298, P61A6) were developed to target downstream oncogenesis of Ras and are potent in inducing apoptosis as well as G1 phase cell-cycle arrest [ 97 ].…”

Section: Targeting the Mevalonate Pathwaymentioning

confidence: 99%

Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

Pereira

Matuszewska

Glogova

et al. 2022

Cancers

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Tumor cells have the ability to co-opt multiple metabolic pathways, enhance glucose uptake and utilize aerobic glycolysis to promote tumorigenesis, which are characteristics constituting an emerging hallmark of cancer. Mutated tumor suppressor and proto-oncogenes are frequently responsible for enhanced metabolic pathway signaling. The link between mutant p53 and the mevalonate (MVA) pathway has been implicated in the advancement of various malignancies, with tumor cells relying heavily on increased MVA signaling to fuel their rapid growth, metastatic spread and development of therapy resistance. Statin drugs inhibit HMG-CoA reductase, the pathway’s rate-limiting enzyme, and as such, have long been studied as a potential anti-cancer therapy. However, whether statins provide additional anti-cancer properties is worthy of debate. Here, we examine retrospective, prospective and pre-clinical studies involving the use of statins in various cancer types, as well as potential issues with statins’ lack of efficacy observed in clinical trials and future considerations for upcoming clinical trials.

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Emerging RAS-directed therapies for cancer

Cited by 10 publications

References 94 publications

Role of RAS signaling in ovarian cancer

Role of RAS signaling in ovarian cancer

Deciphering Regulatory Proteins of Prenylated Protein via the FRET Technique Using Nitroso-Based Ene-Ligation and Sequential Azidation and Click Reaction

Mutant p53, the Mevalonate Pathway and the Tumor Microenvironment Regulate Tumor Response to Statin Therapy

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