Silencing of Oncogenic KRAS by Mutant-Selective Small Interfering RNA

Papke, Bjoern; Azam, Salma H.; Feng, Anne Y.; Gutierrez-Ford, Christina; Huggins, Hayden P; Pallan, Pradeep S.; Swearingen, Amanda E.D. Van; Egli, Martin; Cox, Adrienne D.; Der, Channing J.; Pecot, Chad V.

doi:10.1021/acsptsci.0c00165

Cited by 11 publications

(13 citation statements)

References 36 publications

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“…However, the crucial, likely rate-determining coupled proton transfer that deprotonates the nucleophilic water and forms the inorganic phosphate ( Figure 3D ) remains controversial [ 32–34 ]. The majority (∼97%) of the oncogenic mutations are concentrated at only three hot spots [ 35 ]: G12 and G13 in the P-loop and Q61 in Switch II, all in close proximity to the reaction site ( Figure 3E ), with Q61 most likely involved in the proton transfer [ 32 ]. Oncogenic mutations can impair the GTPase activity of the RAS–GAP complex, although the precise mechanisms are not yet established.…”

Section: Dynamic Regulation Of Ras Activity Operating At the Gdp–gtp ...mentioning

confidence: 99%

Dynamic regulation of RAS and RAS signaling

Kölch

Berta

Rosta

2023

Biochemical Journal

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RAS proteins regulate most aspects of cellular physiology. They are mutated in 30% of human cancers and 4% of developmental disorders termed Rasopathies. They cycle between active GTP-bound and inactive GDP-bound states. When active, they can interact with a wide range of effectors that control fundamental biochemical and biological processes. Emerging evidence suggests that RAS proteins are not simple on/off switches but sophisticated information processing devices that compute cell fate decisions by integrating external and internal cues. A critical component of this compute function is the dynamic regulation of RAS activation and downstream signaling that allows RAS to produce a rich and nuanced spectrum of biological outputs. We discuss recent findings how the dynamics of RAS and its downstream signaling is regulated. Starting from the structural and biochemical properties of wild-type and mutant RAS proteins and their activation cycle, we examine higher molecular assemblies, effector interactions and downstream signaling outputs, all under the aspect of dynamic regulation. We also consider how computational and mathematical modeling approaches contribute to analyze and understand the pleiotropic functions of RAS in health and disease.

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Section: Dynamic Regulation Of Ras Activity Operating At the Gdp–gtp ...mentioning

confidence: 99%

Dynamic regulation of RAS and RAS signaling

Kölch

Berta

Rosta

2023

Biochemical Journal

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“…Clinical data from CodeBreak 100/101 revealed promising efficacy with long-lasting anti-tumor effects when a programmed cell death protein 1 (PD-1) antibody was administered alongside a KRASG 12 C inhibitor, suggesting that PD-1 inhibition produces a synergistic effect with sotorasib and enhances CD8-positive T-cell infiltration, which causes an inhibition of tumor growth [ 83 – 87 ]. In addition, there is substantial evidence that the co-delivery of siRNA that shows specific binding to mRNA of the most commonly occurring KRAS missense mutations together with a chemical EGFR inhibitor may efficiently reduce mutant KRAS-induced effects and may contribute to overcoming resistance in the treatment of NSCLC [ 72 , 88 – 89 ].…”

Section: Reviewmentioning

confidence: 99%

Nanotechnology – a robust tool for fighting the challenges of drug resistance in non-small cell lung cancer

Gorachinov¹,

Mraiche²,

Moustafa³

et al. 2023

Beilstein J. Nanotechnol.

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Genomic and proteomic mutation analysis is the standard of care for selecting candidates for therapies with tyrosine kinase inhibitors against the human epidermal growth factor receptor (EGFR TKI therapies) and further monitoring cancer treatment efficacy and cancer development. Acquired resistance due to various genetic aberrations is an unavoidable problem during EGFR TKI therapy, leading to the rapid exhaustion of standard molecularly targeted therapeutic options against mutant variants. Attacking multiple molecular targets within one or several signaling pathways by co-delivery of multiple agents is a viable strategy for overcoming and preventing resistance to EGFR TKIs. However, because of the difference in pharmacokinetics among agents, combined therapies may not effectively reach their targets. The obstacles regarding the simultaneous co-delivery of therapeutic agents at the site of action can be overcome using nanomedicine as a platform and nanotools as delivery agents. Precision oncology research to identify targetable biomarkers and optimize tumor homing agents, hand in hand with designing multifunctional and multistage nanocarriers that respond to the inherent heterogeneity of the tumors, may resolve the challenges of inadequate tumor localization, improve intracellular internalization, and bring advantages over conventional nanocarriers.

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“…As such, the delivery of EFTX-D1, a siRNA selectively targeting the most common mutated KRAS genes such as G12C, G12D, and G13D, has been explored as a therapeutic approach. EFTX-D1 was able to decrease both the levels of oncogenic KRAS mRNA and protein levels, but in vivo preclinical trials are yet to be conducted ( Papke et al, 2021 ). In agreement with Papke et al, the authors agree that the nanoparticle delivery of EFTX-D1 using iExosomes will be the next step to evaluate the KRAS inhibitor’s performance, possibly in combination with ICIs.…”

Section: Exosomesmentioning

confidence: 99%

Key Players of the Immunosuppressive Tumor Microenvironment and Emerging Therapeutic Strategies

Park

Veena

Shin

2022

Front. Cell Dev. Biol.

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The tumor microenvironment (TME) is a complex, dynamic battlefield for both immune cells and tumor cells. The advent of the immune checkpoint inhibitors (ICI) since 2011, such as the anti-cytotoxic T-lymphocyte associated protein (CTLA)-4 and anti-programmed cell death receptor (PD)-(L)1 antibodies, provided powerful weapons in the arsenal of cancer treatments, demonstrating unprecedented durable responses for patients with many types of advanced cancers. However, the response rate is generally low across tumor types and a substantial number of patients develop acquired resistance. These primary or acquired resistance are attributed to various immunosuppressive elements (soluble and cellular factors) and alternative immune checkpoints in the TME. Therefore, a better understanding of the TME is absolutely essential to develop therapeutic strategies to overcome resistance. Numerous clinical studies are underway using ICIs and additional agents that are tailored to the characteristics of the tumor or the TME. Some of the combination treatments are already approved by the Food and Drug Administration (FDA), such as platinum-doublet chemotherapy, tyrosine kinase inhibitor (TKI) -targeting vascular endothelial growth factor (VEGF) combined with anti-PD-(L)1 antibodies or immuno-immuno combinations (anti-CTLA-4 and anti-PD-1). In this review, we will discuss the key immunosuppressive cells, metabolites, cytokines or chemokines, and hypoxic conditions in the TME that contribute to tumor immune escape and the prospect of relevant clinical trials by targeting these elements in combination with ICIs.

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Silencing of Oncogenic KRAS by Mutant-Selective Small Interfering RNA

Cited by 11 publications

References 36 publications

Dynamic regulation of RAS and RAS signaling

Dynamic regulation of RAS and RAS signaling

Nanotechnology – a robust tool for fighting the challenges of drug resistance in non-small cell lung cancer

Key Players of the Immunosuppressive Tumor Microenvironment and Emerging Therapeutic Strategies

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