BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy

Li, Zinan; Zhao, Lin; Yu, Lifeng; Wei, Minjie

doi:10.1093/gastro/goaa022

Cited by 76 publications

(55 citation statements)

References 161 publications

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“…Almost all of these K-ras mutations occur in codons 12 or 13 [ 6 ]. K-ras is the most common oncogene in the well-studied rat sarcoma virus (RAS) subfamily proteins because of its significant role in cancer [ 7 ]. Wild type or unmutated K-ras protein resides in the GDP-bound state on the plasma membrane in quiescent cells (i.e inactive).…”

Section: Introductionmentioning

confidence: 99%

Clinico-Pathological Study of K-ras Mutations in Colorectal Tumors: A Single-Center Retrospective Study of 51 Patients in Madinah, Saudi Arabia

Mulla¹,

Alshareef²,

Syed

et al. 2020

Cureus

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Background Colorectal cancer (CRC) is one of the leading types of cancer worldwide and in Saudi Arabia. At the molecular level, CRC is very complicated and requires establishing comprehensive patient stratification models through identification of patients who will benefit or will not benefit from targeted therapy. We retrospectively investigated and analyzed the frequency of Kirsten-ras (K-ras) mutation and its correlation with patients’ characteristics as weel as its association with clinicopathological features (i.e age, gender, clinical stage, anatomical site, histological subtype, degree of histological differentiation and metastatic site) in patients with CRC. Methods Medical records and paraffin-embedded tumor samples from 51 patients with histologically proven colorectal adenocarcinoma referred to Madinah center in Saudi Arabia were analyzed for the occurrence of rat sarcoma virus (RAS) mutations. Results RAS mutations occurred in 43% of the patients; 91% of these mutations were in K-ras. Seventy-five percent of these K-ras mutations were in codon 12, most commonly p.G12D. Codon 13 mutations occurred in 20% of tumors: all of these were p.G13D (100%). The percentage of K-ras mutations occurrence was higher in young patients (≤50) compared with the older patients (>50) (54.5% and 35%, respectively). Similarly, the percentage of K-ras mutations occurrence was higher in the right-sided tumors compared with the left-sided tumors (57.1% and 32.4%, respectively). Patients’ characteristics and clinicopathological features were not significantly associated with K-ras mutations. Conclusions K-ras mutations are common among Saudi patients diagnosed with CRC in Madinah, especially pG12V and pG12D in codon 12. Further investigation would be required to establish correlation of K-ras mutations in larger cohorts.

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Section: Introductionmentioning

confidence: 99%

Clinico-Pathological Study of K-ras Mutations in Colorectal Tumors: A Single-Center Retrospective Study of 51 Patients in Madinah, Saudi Arabia

Mulla¹,

Alshareef²,

Syed

et al. 2020

Cureus

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“…Mutations in the RAS family genes are a common finding in CRC, with KRAS being the most common (85%), followed by NRAS (15%), and HRAS (1%) [ 63 ]. KRAS mutations occur in approximately 44% of metastatic CRC (mCRC), with the majority being observed in codons 12 and 13 of exon 2 (80% are G12D, G12V, G12C, G12A, and G13D), and less frequently in codon 61 of exon 3 (5% are Q61H, Q61L, and Q61R) and codon 146 of exon 4 (2% are A146T and A146V) [ 63 ]. KRAS codon 12 or 13 mutations are a major predictive biomarker for resistance to anti-EGFR therapy in patients with mCRC, thus being recognized as a negative prognostic factor [ 64 ].…”

Section: Colorectal Cancermentioning

confidence: 99%

Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors

et al. 2021

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Activating mutations in RAS family proteins are found in ~25% of all human cancers. Different solid tumors are correlated with mutations in certain isoforms of RAS, with Kirsten RAS (KRAS) being the most frequently mutated isoform. Historically, KRAS has been acknowledged as “undruggable”, largely because the RAS proteins do not appear to present suitable pockets to which small inhibitory molecules can bind. However, this scenario has changed over the last years with the advent of novel KRAS inhibitors. In this review, we describe the role of KRAS mutation across different solid tumors, providing data on novel KRAS inhibitors currently under development and an updated overview of ongoing research in this field. A literature search was performed to select papers, abstracts, and oral presentation on KRAS inhibitory strategies in KRAS mutated solid tumors. Overall, the most promising therapeutic results have been obtained with molecules targeting KRAS G12C, thus paving the way for a significant therapeutic improvement in non-small cell lung cancer. Unfortunately, KRAS G12C mutation is rather uncommon in other solid tumors, namely pancreatic ductal adenocarcinoma and colorectal cancer. Several combination strategies are currently under evaluation in clinical trials, in order to bypass the resistance mechanisms responsible for the intrinsic resistance of mutated KRAS to the main therapeutic strategies adopted to date. Results suggest that the therapeutic scenario of KRAS has started to change, and further research will bring therapeutic results in this field.

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“…BRAF is a proto-oncogene acting in cell growth. CRC patients with the BRAF mutation have a lower survival rate than their non-mutated counterparts, and this can be used as a predictive marker in chemotherapy of CRC [168]. Around 8-10% of metastatic CRC show mutations of the BRAF gene, which is associated with reduced prognosis of these patients [154,158,160].…”

Section: Patient-derived Tumoroidsmentioning

confidence: 99%

Characterization of in vitro 3D cultures

Mousavi

2021

APMIS

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SummaryOver the past decade, 3D culture models of human and animal cells have found their way into tissue differentiation, drug development, personalized medicine and tumour behaviour studies. Embryoid bodies (EBs) are in vitro 3D cultures established from murine pluripotential stem cells, whereas tumoroids are patient‐derived in vitro 3D cultures. This thesis aims to describe a new implication of an embryoid body model and to characterize the patient‐specific microenvironment of the parental tumour in relation to tumoroid growth rate. In this thesis, we described a high‐throughput monitoring method, where EBs are used as a dynamic angiogenesis model. In this model, digital image analysis (DIA) is implemented on immunohistochemistry (IHC) stained sections of the cultures over time. Furthermore, we have investigated the correlation between the genetic profile and inflammatory microenvironment of parental tumours on the in vitro growth rate of tumoroids. The EBs were cultured in spinner flasks. The samples were collected at days 4, 6, 9, 14, 18 and 21, dehydrated and embedded in paraffin. The histological sections were IHC stained for the endothelial marker CD31 and digitally scanned. The virtual whole‐image slides were digitally analysed by Visiopharm® software. Histological evaluation showed vascular‐like structures over time. The quantitative DIA was plausible to monitor significant increase in the total area of the EBs and an increase in endothelial differentiation. The tumoroids were established from 32 colorectal adenocarcinomas. The in vitro growth rate of the tumoroids was followed by automated microscopy over an 11‐day period. The parental tumours were analysed by next‐generation sequencing for KRAS, TP53, PIK3CA, SMAD4, MAP2K1, BRAF, FGFR3 and FBXW7 status. The tumoroids established from KRAS‐mutated parental tumours showed a significantly higher growth rate compared to their wild‐type counterparts. The density of CD3+ T lymphocytes and CD68+ macrophages was calculated in the centre of the tumours and at the invasive margin of the tumours. The high density of CD3+ cells and the low density of CD68+ cells showed a significant correlation with a higher growth rate of the tumoroids. In conclusion, a novel approach for histological monitoring of endothelial differentiation is presented in the stem cell‐derived EBs. Furthermore, the KRAS status and density of CD3+ T cells and macrophages in the parental tumour influence the growth rate of the tumoroids. Our results indicate that these parameters should be included when tumoroids are to be implemented in personalized medicine

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BRAF and KRAS mutations in metastatic colorectal cancer: future perspectives for personalized therapy

Cited by 76 publications

References 161 publications

Clinico-Pathological Study of K-ras Mutations in Colorectal Tumors: A Single-Center Retrospective Study of 51 Patients in Madinah, Saudi Arabia

Clinico-Pathological Study of K-ras Mutations in Colorectal Tumors: A Single-Center Retrospective Study of 51 Patients in Madinah, Saudi Arabia

Targeting KRAS in Solid Tumors: Current Challenges and Future Opportunities of Novel KRAS Inhibitors

Characterization of in vitro 3D cultures

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