Non-Redundant and Overlapping Oncogenic Readouts of Non-Canonical and Novel Colorectal Cancer KRAS and NRAS Mutants

Alcantara, Krizelle Mae M.; Malapit, Joshua Reginald P.; Yu, Ryan Timothy D.; Garrido, Jose Antonio Ma. G.; Rigor, John Paul T.; Angeles, Arlou Kristina; Paz, Eva Maria Cutiongco‐de la; Garcia, Reynaldo L.

doi:10.3390/cells8121557

Cited by 10 publications

(7 citation statements)

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“…This study reveals the first and unexpected causal link between KRAS or BRAF mutations and hepatic vascular cavernomas. Mutations in RAS, the first human oncogene, and BRAF genes drive ∼30% of human tumors ( Alcantara et al, 2019 ; Hunter et al, 2015 ; Lu et al, 2016 ; Smith et al, 2013 ; Der et al, 1982 ; Zhong et al, 1999 ; Davies et al, 2002 ; Thomas et al, 2007 ), yet no reports describe RAS or RAF mutations in hepatic cavernous hemangiomas, the most common benign tumor of the liver. We identified somatic activating KRAS and/or BRAF mutations in human hepatic tissue samples with sporadic hemangioma lesion ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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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“…Riquelme et al also confirmed that not all oncogenic K-Ras mutants activate and enhance MAPK signaling by showing that the level of phospho-MEK1/2 is increased in NSCLC cells harboring the KRAS G12C and KRAS G12D mutations but decreased in cells harboring the KRAS G12R and G12S [3]. By contrast, a recent study using NIH3T3 cells showed that KRAS G12S-expressing cells had elevated p-ERK levels, suggesting that this mutant in this setting exerts its oncogenic phenotype via MAPK signaling [6].…”

Section: The Mapk Pathwaymentioning

confidence: 67%

The effects of mutant Ras proteins on the cell signalome

Takács

Kudlik

Kurilla

et al. 2020

Cancer Metastasis Rev

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The genetic alterations in cancer cells are tightly linked to signaling pathway dysregulation. Ras is a key molecule that controls several tumorigenesis-related processes, and mutations in RAS genes often lead to unbiased intensification of signaling networks that fuel cancer progression. In this article, we review recent studies that describe mutant Ras-regulated signaling routes and their cross-talk. In addition to the two main Ras-driven signaling pathways, i.e., the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we have also collected emerging data showing the importance of Ras in other signaling pathways, including the RAC/ PAK, RalGDS/Ral, and PKC/PLC signaling pathways. Moreover, microRNA-regulated Ras-associated signaling pathways are also discussed to highlight the importance of Ras regulation in cancer. Finally, emerging data show that the signal alterations in specific cell types, such as cancer stem cells, could promote cancer development. Therefore, we also cover the up-to-date findings related to Ras-regulated signal transduction in cancer stem cells.

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“…What has been reported is that cells with A59T, as with a select few other forms of KRAS and NRAS , have higher rates of cell proliferation and migration in vitro; furthermore, A59T deregulates extracellular signal-related kinase (ERK) and the downstream target ETS transcription factor ELK1. Based on reports to date, it is clear that the role of A59T as a molecular regulator is quite different than other, more well-characterized and more common forms of RAS [ 11 ]. The A59T mutation reduces GTPase activity fivefold [ 12 ] and doubles the nucleotide exchange rate compared to wild-type RAS .…”

Section: Discussionmentioning

confidence: 99%

Expression of Immuno-Oncologic Biomarkers Is Enriched in Colorectal Cancers and Other Solid Tumors Harboring the A59T Variant of KRAS

Lou

Xiu

Baca

et al. 2021

Cells

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The molecular heterogeneity of KRAS is well established, with a pool of variants comprising >75% of all known mutations; this pool includes mutations in classic codons 12, 13, and 61, as well as 146 and 117. In addition, there are rare variants that are more frequently encountered clinically due to the advances in next-generation sequencing and more widespread implementation of All-RAS sequencing over the past five years. We have previously identified a missense variant of KRAS, A59T, in a patient with CRC that was associated with a response to an epidermal growth factor inhibitor when added to chemotherapy, supporting the hypothesis that distinct biochemical impacts of different KRAS mutations may produce varied responses to targeted therapy. In this study, we explored a large genomic database comprising 17,909 cases of CRC to determine the prevalence of the A59T mutation and characterized the concurrent genomic alterations associated with this variant in more detail, particularly in relation to the expanding set of potential predictive immuno-oncologic biomarkers. We identified 14 cases of A59 mutations in this dataset (0.08% prevalence). We evaluated the prevalence of high tumor mutation burden (TMB), positive PD-L1 expression, and microsatellite instability-high/mismatch repair-deficiency (MSI-H/dMMR) using both next generation sequencing (NGS) and immunohistochemistry (IHC). The genomic features of pertinent signaling pathways were also described, including RAS pathway, chromatin remodeling, DDR, hedgehog signaling, PI3K, receptor tyrosine kinases, signal transduction, TGF-beta, TP53, and WNT. We uncovered a high level of association of predictive markers of responsiveness to checkpoint inhibition and potentially other forms of immunotherapy, with nearly half of all cases harboring microsatellite instability as assessed using NGS. A59T was also detected in 11 additional cancer types, most prominently in cases of gynecologic or other gastrointestinal sites of origin. This study provides supportive evidence that A59T, and possibly other similarly rare KRAS variants, co-occur with predictive biomarkers of response to immunotherapy.

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Non-Redundant and Overlapping Oncogenic Readouts of Non-Canonical and Novel Colorectal Cancer KRAS and NRAS Mutants

Cited by 10 publications

References 50 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

The effects of mutant Ras proteins on the cell signalome

Expression of Immuno-Oncologic Biomarkers Is Enriched in Colorectal Cancers and Other Solid Tumors Harboring the A59T Variant of KRAS

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