RAS Mutations Are Not Created Equal

Hobbs, G. Aaron; Der, Channing J.

doi:10.1158/2159-8290.cd-19-0406

Cited by 26 publications

(30 citation statements)

References 10 publications

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“…S3). These data and previous literature reports suggest structural, biochemical, and functional similarities among KRAS G12/13 and BRAF V600 mutations (Yao et al, 2015;Smith et al, 2013;Lu et al, 2016;Hunter et al, 2015;Hobbs et al, 2016;Hobbs and Der, 2019). For example, KRAS G12D, G12C, and G12V mutations exhibit similar crystal structure and hyperactivate RAS, leading to sustained activation of the RAF-MAP2K-MAPK1 signaling pathway (Li et al, 2018;Muñoz-Maldonado et al, 2019;Johnson et al, 2019;Ihle et al, 2012;Hobbs et al, 2016;Hunter et al, 2015;Smith et al, 2013;Lu et al, 2016).…”

Section: Discussionsupporting

confidence: 83%

KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K–MAPK1 inhibition

Janardhan

Meng

Dresser

et al. 2020

Journal of Experimental Medicine

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Human hepatic vascular cavernomas, the most common benign tumor of the liver, were described in the mid-1800s, yet the mechanisms for their formation and effective treatments remain unknown. Here, we demonstrate gain-of-function mutations in KRAS or BRAF genes within liver endothelial cells as a causal mechanism for hepatic vascular cavernomas. We identified gain-of-function mutations in KRAS or BRAF genes in pathological liver tissue samples from patients with hepatic vascular cavernomas. Mice expressing these human KRASG12D or BRAFV600E mutations in hepatic endothelial cells recapitulated the human hepatic vascular cavernoma phenotype of dilated sinusoidal capillaries with defective branching patterns. KRASG12D or BRAFV600E induced “zipper-like” contiguous expression of junctional proteins at sinusoidal endothelial cell–cell contacts, switching capillaries from branching to cavernous expansion. Pharmacological or genetic inhibition of the endothelial RAS–MAPK1 signaling pathway rescued hepatic vascular cavernoma formation in endothelial KRASG12D- or BRAFV600E-expressing mice. These results uncover a major cause of hepatic vascular cavernomas and provide a road map for their personalized treatment.

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Section: Discussionsupporting

confidence: 83%

KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K–MAPK1 inhibition

Janardhan

Meng

Dresser

et al. 2020

Journal of Experimental Medicine

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“…Furthermore, both KRAS and HRAS have higher activity toward NFκB activation in contrast to NRAS [37]. While being members of the most frequently mutated oncogene family in human cancer [38], RAS isoform mutants are clearly not equally prevalent in cancers [30]. KRAS mutations are overwhelmingly represented in cancers as whole compared to the other two isoforms.…”

Section: Ras Gtpases and Their Activationmentioning

confidence: 99%

“…The mammalian RAS GTPases consist of three gene isoforms, HRAS, NRAS, and KRAS, and four protein isoforms (splicing isoforms of KRAS give rise to KRAS4A and KRAS4B proteins). Whilst the isoforms share most of their sequence, substantial differences appear in the C-terminal so-called hypervariable regions and in post-translational modifications [28][29][30]. These differences in sequence and modification are considered to underlie the findings that RAS isoforms can function differentially in different biology and pathophysiology [31][32][33][34][35].…”

Section: Ras Gtpases and Their Activationmentioning

confidence: 99%

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Degirmenci

Wang

2020

Cells

399

303

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The RAS/RAF/MEK/ERK (MAPK) signaling cascade is essential for cell inter- and intra-cellular communication, which regulates fundamental cell functions such as growth, survival, and differentiation. The MAPK pathway also integrates signals from complex intracellular networks in performing cellular functions. Despite the initial discovery of the core elements of the MAPK pathways nearly four decades ago, additional findings continue to make a thorough understanding of the molecular mechanisms involved in the regulation of this pathway challenging. Considerable effort has been focused on the regulation of RAF, especially after the discovery of drug resistance and paradoxical activation upon inhibitor binding to the kinase. RAF activity is regulated by phosphorylation and conformation-dependent regulation, including auto-inhibition and dimerization. In this review, we summarize the recent major findings in the study of the RAS/RAF/MEK/ERK signaling cascade, particularly with respect to the impact on clinical cancer therapy.

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“…There is controversy among some experts who analyze the ovarian cancer prognosis associated with KRAS mutation. One researcher declared that KRAS mutation can occur at an early stage of ovarian cancer and had a good prognosis, on the other hand, there were researchers who reported that the KRAS mutation was associated with high recurrence rate and poor prognosis [5], [6]. The aim of this study is to prove that staging, grading, and KRAS exon 2 mutations will influence recurrence in epithelial ovarian cancer.…”

Section: Introductionmentioning

confidence: 90%

Analysis of Clinicopathologic Factors and KRAS Gene Mutation in Epithelial Ovarian Cancer Outcomes

Friadi¹,

Harahap²,

Almasi‐Hashiani³

et al. 2020

Open Access Maced J Med Sci

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BACKGROUND: Raise of ovarian cancer mortality is caused by high ovarian cancer recurrence. This is related to many prognostic factors. Kirsten-rat sarcoma virus oncogene (KRAS) is a proto-oncogene that regulates proliferation, growth and cell motility. The controversy of some experts regarding KRAS mutations in the prognosis of ovarian cancer makes it interesting to analyze. AIM: The aim of this study is to clarify whether the clinicopathologic factors and KRAS gene mutation affect the recurrence of patients with ovarian cancer in Indonesia. METHODS: The authors conducted a retrospective cohort study. Clinicopathological factors and prognoses were obtained for 205 patients who were histopathologically diagnosed with epithelial ovarian cancer or ovarian borderline malignant tumor, operated from June 2015 to January 2019 at Dr. M. Djamil General Hospital. We gathered 80 patients who were diagnosed with epithelial ovarian cancer since June 2015 until January 2019. These cases were analyzed after 2-year follow-up or recurrence occurred. Survival rate was determined using the Kaplan–Meier method and examined by Log rank test. All analyses were performed using STATA ver. 12.0, with p < 0.05 considered to be significant. RESULTS: Among KRAS mutation group, the 2-year disease free survival rate (2y-DFS) was 31.56% and 47.58% in non-mutation group with significant differences between mutation and non-mutation (p = 0.02). There was a significant difference between early stage ovarian cancer with non-mutation group and advanced stages ovarian cancer with mutation group (p = 0.00). Among combination staging with mutation group, the 2y-DFS was 85.79% in early stage ovarian cancer with non-mutation, 44.44% in early stage with mutation, 10.65% in advanced stage with non-mutation, and 20.00% in advanced stage with mutation. CONCLUSION: The results suggest that staging and KRAS mutation are the most influence prognostic factors for epithelial ovarian cancer. There was a discrepancy of prognosis by staging and mutation between early stage with non-mutation and advanced stage with KRAS mutation.

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RAS Mutations Are Not Created Equal

Cited by 26 publications

References 10 publications

KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K–MAPK1 inhibition

KRAS or BRAF mutations cause hepatic vascular cavernomas treatable with MAP2K–MAPK1 inhibition

Targeting Aberrant RAS/RAF/MEK/ERK Signaling for Cancer Therapy

Analysis of Clinicopathologic Factors and KRAS Gene Mutation in Epithelial Ovarian Cancer Outcomes

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