RASpecting the oncogene: New pathways to therapeutic advances

Stout, Matthew C.; Campbell, Paul M.

doi:10.1016/j.bcp.2018.10.022

Cited by 6 publications

(6 citation statements)

References 94 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…HRAS is the least common cancer-associated Ras's isoform, and it is found mostly in cancers of the urinary tract, such as bladder cancer. The most common mutation sites in all three canonical Ras proteins are codons 12, 13 or 61 (22).…”

Section: Rasmentioning

confidence: 99%

Everything Old Is New Again: Drug Repurposing Approach for Non-Small Cell Lung Cancer Targeting MAPK Signaling Pathway

et al. 2021

View full text Add to dashboard Cite

Non-small cell lung cancer (NSCLC) is a prominent subtype of lung carcinoma that accounts for the majority of cancer-related deaths globally, and it is responsible for about 80% to 85% of lung cancers. Mitogen-Activated Protein Kinase (MAPK) signaling pathways are a vital aspect of NSCLC, and have aided in the advancement of therapies for this carcinoma. Targeting the Ras/Raf/MEK/ERK pathway is a promising and alternative method in NSCLC treatment, which is highlighted in this review. The introduction of targeted medicines has revolutionized the treatment of patients with this carcinoma. When combined with current systems biology-driven stratagems, repurposing non-cancer drugs into new therapeutic niches presents a cost-effective and efficient technique with enhancing outcomes for discovering novel pharmacological activity. This article highlights the successful cutting-edge techniques while focusing on NSCLC targeted therapies. The ultimate challenge will be integrating these repurposed drugs into the therapeutic regimen of patients affected with NSCLC to potentially increase lung cancer cure rates.

show abstract

Section: Rasmentioning

confidence: 99%

Everything Old Is New Again: Drug Repurposing Approach for Non-Small Cell Lung Cancer Targeting MAPK Signaling Pathway

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The cells were then stimulated with stem cell factor (SCF) and GM-CSF and subjected to flow cytometric analysis to analyze the phosphorylation status of ERK, AKT and ribosomal S6 (an AKT effector) in the HSPC-enriched lineage-negative (Lin-) compartment. Figures 3D and E show that treatment with RGS attenuated the phosphorylation of both ERK, AKT and S6, proteins whose functions are regulated by RAS [21,22] and are activated in Mx1cre-Kas +/G12D mice [16]. We also examined the phosphorylation status of STAT5, which has recently been shown to mediate the phenotypes observed in mutant and hyperactive K- and NRAS-driven hematopoietic phenotypes in animal models [16, 19, 23- 26] and is often aberrantly activated in JMML and other myeloid malignant cells treated with low concentrations of GM-CSF [25].…”

Section: Resultsmentioning

confidence: 99%

Rigosertib ameliorates the effects of oncogenic KRAS signaling in a murine model of myeloproliferative neoplasia

et al. 2019

View full text Add to dashboard Cite

Aberrant signaling triggered by oncogenic or hyperactive RAS proteins contributes to the malignant phenotypes in a significant percentage of myeloid malignancies. Of these, juvenile myelomonocytic leukemia (JMML), an aggressive childhood cancer, is largely driven by mutations in RAS genes and those that encode regulators of these proteins. The Mx1-cre kras +/G12D mouse model mirrors several key features of this disease and has been used extensively to determine the utility and mechanism of small molecule therapeutics in the context of RAS-driven myeloproliferative disorders. Treatment of disease-bearing KRAS G12D mice with rigosertib (RGS), a small molecule RAS mimetic that is in phase II and III clinical trials for MDS and AML, decreased the severity of leukocytosis and splenomegaly and extended their survival. RGS also increased the frequency of HSCs and rebalanced the ratios of myeloid progenitors. Further analysis of KRAS G12D HSPCs in vitro revealed that RGS suppressed hyperproliferation in response to GM-CSF and inhibited the phosphorylation of key RAS effectors. Together, these data suggest that RGS might be of clinical benefit in RAS-driven myeloid disorders.

show abstract

“…Altogether, mechanistic underpinnings that decide the mutational effects—whether statistically frequent or rare, at the tail of the distribution—can involve orthosteric or allosteric effects (Cheng and Nussinov 2018 ; Cheng et al 2016 ; Collier and Ortiz 2013 ; Feher et al 2014 ; Fetics et al 2015 ; Liu and Nussinov 2008 ; Lu et al 2015 , 2016a , b ; Marcus and Mattos 2015 ; Morra et al 2009 ; Munro et al 2018 ; Nikolaev et al 2018 ; Park et al 2018 ; Risques and Kennedy 2018 ; Shen et al 2017 ; Stout and Campbell 2018 ; Tehver et al 2009 ; Tsai and Nussinov 2014 , 2017 ; Tuncbag et al 2017 ; Waters and Der 2018 ; Xu et al 2017 ; Zhan et al 2016 ). Orthosteric mutations are at binding or active sites and can directly abolish (most frequent) or strengthen (much less frequent) interactions.…”

Section: How Biophysics Can Empower Concepts and Approaches In Precismentioning

confidence: 99%

Precision medicine review: rare driver mutations and their biophysical classification

et al. 2019

View full text Add to dashboard Cite

How can biophysical principles help precision medicine identify rare driver mutations? A major tenet of pragmatic approaches to precision oncology and pharmacology is that driver mutations are very frequent. However, frequency is a statistical attribute, not a mechanistic one. Rare mutations can also act through the same mechanism, and as we discuss below, Blatent driver^mutations may also follow the same route, with Bhelper^mutations. Here, we review how biophysics provides mechanistic guidelines that extend precision medicine. We outline principles and strategies, especially focusing on mutations that drive cancer. Biophysics has contributed profoundly to deciphering biological processes. However, driven by data science, precision medicine has skirted some of its major tenets. Data science embodies genomics, tissue-and cell-specific expression levels, making it capable of defining genome-and systems-wide molecular disease signatures. It classifies cancer driver genes/mutations and affected pathways, and its associated protein structural data guide drug discovery. Biophysics complements data science. It considers structures and their heterogeneous ensembles, explains how mutational variants can signal through distinct pathways, and how allo-network drugs can be harnessed. Biophysics clarifies how one mutation-frequent or rare-can affect multiple phenotypic traits by populating conformations that favor interactions with other network modules. It also suggests how to identify such mutations and their signaling consequences. Biophysics offers principles and strategies that can help precision medicine push the boundaries to transform our insight into biological processes and the practice of personalized medicine. By contrast, Bphenotypic drug discovery,^which capitalizes on physiological cellular conditions and first-in-class drug discovery, may not capture the proper molecular variant. This is because variants of the same protein can express more than one phenotype, and a phenotype can be encoded by several variants.

show abstract

RASpecting the oncogene: New pathways to therapeutic advances

Cited by 6 publications

References 94 publications

Everything Old Is New Again: Drug Repurposing Approach for Non-Small Cell Lung Cancer Targeting MAPK Signaling Pathway

Everything Old Is New Again: Drug Repurposing Approach for Non-Small Cell Lung Cancer Targeting MAPK Signaling Pathway

Rigosertib ameliorates the effects of oncogenic KRAS signaling in a murine model of myeloproliferative neoplasia

Precision medicine review: rare driver mutations and their biophysical classification

Contact Info

Product

Resources

About