BRAF provides proliferation and survival signals in MSI colorectal carcinoma cells displaying BRAFV600E but not KRAS mutations

Preto, Ana; Figueiredo, Joana; Velho, Sérgia; Ribeiro, Ana M.; Soares, Paula; Oliveira, Carla; Seruca, Raquel

doi:10.1002/path.2295

Cited by 53 publications

(31 citation statements)

References 29 publications

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“…This frequency increases to 70% in colorectal cancers with a microsatellite instability (MSI) phenotype due to hypermethylation of the MLH1 promoter [41][42][43]. In MSI colorectal carcinoma, BRAF mutations occur independently of KRAS mutations and provide proliferation and survival signals through activation of several signaling pathways [44,45]. Cell lines with RAS/BRAF mutations are highly resistant to cetuximab in vitro compared with wild-type cells [46].…”

Section: Biomarkers In Colorectal Cancermentioning

confidence: 99%

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

et al. 2008

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Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with colorectal carcinoma. However, these therapies are effective only in a subset of patients. Activating mutations in the KRAS gene are found in 30-40% of colorectal tumors and are associated with poor response to anti-EGFR therapies. Thus, KRAS mutation status can predict which patient may or may not benefit from anti-EGFR therapy. Although many diagnostic tools have been developed for KRAS mutation analysis, validated methods and standardized testing procedures are lacking. This poses a challenge for the optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatment conferred by KRAS mutations. We also present guideline recommendations and a proposal for a European quality assurance program to help ensure accuracy and proficiency in KRAS mutation testing across the European Union.

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Section: Biomarkers In Colorectal Cancermentioning

confidence: 99%

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

et al. 2008

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“…BRAF inhibition by small interfering RNA resulted in significantly decreased proliferation and increased apoptosis in the BRAF mutant lines. In contrast, this effect was not seen in the KRAS mutant lines (Preto et al, 2008). Cells carrying BRAF mutations have also been shown to be more sensitive to IOSE29 OSE10 OSE7 SKOV3 OVCAR3 A2780 OVK18 KF28 MDAH2774 OMC3 JHOC5 ES2 MPSC1 POC1 POC2 POC3 WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT WT T1796A T1796A WT WT G35T WT WT G35T MEK inhibitors than cells with RAS mutations (Solit et al, 2006).…”

Section: Discussionmentioning

confidence: 98%

KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer

Nakayama

Yeasmin

et al. 2008

Br J Cancer

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This study examined the status of KRAS and BRAF mutations, in relation to extracellular signal-regulated protein kinase (ERK) activation in 58 ovarian carcinomas to clarify the clinicopathological and prognostic significance of KRAS/BRAF mutations. Somatic mutations of either KRAS or BRAF were identified in 12 (20.6%) out of 58 ovarian carcinomas. The frequency of KRAS/BRAF mutations in conventional serous high-grade carcinomas (4.0% : 1/25) was significantly lower than that in the other histological type (32.3% : 10/31). Phosphorylated ERK1/2 (p-ERK1/2) expression was identified in 18 (38.2%) out of 45 ovarian carcinomas. KRAS/BRAF mutation was significantly correlated with International Federation of Gynecology and Obstetrics (FIGO) stage I, II (Po0.001), and p-ERK1/2 (Po0.001). No significant correlations between KRAS/BRAF mutations or p-ERK1/2 expression and overall survival were found in patients with ovarian carcinoma treated with platinum and taxane chemotherapy (P ¼ 0.2460, P ¼ 0.9339, respectively). Next, to clarify the roles of ERK1/2 activation in ovarian cancers harbouring KRAS or BRAF mutations, we inactivated ERK1/2 in ovarian cancer cells using CI-1040. Cl-1040 is a compound that selectively inhibits MAP kinase kinase (MEK), an upstream regulator of ERK1/2, and thus prevents ERK1/2 activation. Profound growth inhibition and apoptosis were observed in CI-1040-treated cancer cells with mutations in either KRAS or BRAF in comparison with the ovarian cancer cells containing wild-type sequences. This was evident in both in vitro and in vivo studies. The findings in this study indicate that an activated ERK1/2 pathway is critical to tumour growth and survival of ovarian cancers with KRAS or BRAF mutations. Furthermore, they suggest that the CI-1040-induced phenotypes depend on the mutational status of KRAS and BRAF in ovarian cancers. Therefore, ovarian cancer patients with KRAS or BRAF mutations may benefit from CI-1040 treatment.

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“…BRAF controls proliferation of human melanoma cells through the regulation of cyclin D1 and cyclindependent kinase inhibitor p27 Kip1 protein (Bhatt et al, 2005(Bhatt et al, , 2007. Similarly, it has been reported that in CRC cells the decreased expression levels of pERK protein and cyclin D1 were more pronounced in cells carrying the BRAF V600E mutation, and, that BRAF V600E -ERK signalling is also important in the regulation of proliferation by p27 Kip1 and cyclin D1 proteins in these cells (Preto et al, 2008).…”

mentioning

confidence: 78%

“…The effect of BRAF knockdown in cellular survival and proliferation is not fully understood. It has been shown that in MSI CRC cell lines, BRAF is the main activator of ERKs and these cells are more dependant on the BRAF -ERK pathway (Preto et al, 2008). Similar to the melanoma model (Bhatt et al, 2005(Bhatt et al, , 2007, in MSI CRC cells, it was shown that BRAF V600E -ERK signalling is important in the regulation of proliferation through the p27 Kip1 and cyclin D1 proteins (Preto et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

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BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome

et al. 2010

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BACKGROUND: The significance of BRAF mutations, microsatelite instability (MSI) status and cyclin D1 expression in patients with metastatic colorectal cancer (mCRC) was evaluated. METHODS: Primary tumours from 144 patients treated for mCRC were assessed for BRAF (V600E) mutation, MSI status and cyclin D1. The data were correlated with progression-free survival (PFS) and overall survival (OS). RESULTS: BRAF mutations were detected in 10 (out of 22, 45%) patients with MSI-H tumours compared with 2 (out of 122, 1.6%) in those with microsatellite stable tumours (Po0.001). The presence of BRAF mutations was correlated with cyclin D1 overexpression (7 out of 26 patients, 58% vs 5 out of 118 patients, 14%; P ¼ 0.001). Patients with BRAF-mutated primary tumours had a significantly decreased PFS (2.7 vs 9.8 months; Po0.001) and median OS (14 vs 30 months; Po0.001) than patients with wild-type (wt) tumours. Patients with MSI-H and BRAF-mutated tumours experienced significantly lower PFS (3.1 vs 11.4 months; P ¼ 0.008) and OS (14.5 vs 35.5 months; P ¼ 0.004) than patients with MSI-H and BRAF wt tumours. Similarly, BRAF mutations and cyclin D1 overexpression were correlated with decreased PFS (3.1 vs 8.6 months; P ¼ 0.03) and OS (17.8 vs 39.2 months; P ¼ 0.01). CONCLUSION: BRAF V600E mutations are associated with MSI-H status and cyclin D1 overexpression and characterize a subgroup of patients with poor prognosis.

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BRAF provides proliferation and survival signals in MSI colorectal carcinoma cells displaying BRAF^V600E but not KRAS mutations

Cited by 53 publications

References 29 publications

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer

BRAF mutations, microsatellite instability status and cyclin D1 expression predict metastatic colorectal patients’ outcome

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