BRAF V600E mutant colorectal cancer subtypes based on gene expression
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75317 | GEO | 2016/11/28
SECONDARY ACCESSION(S): PRJNA303175
REPOSITORIES: GEO
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Project description:BRAF V600E mutant colorectal cancer subtypes based on gene expression
| PRJNA303175 | ENA
Project description:BackgroundCombinatorial inhibition of epidermal growth factor receptor (EGFR) and BRAF shows remarkable clinical benefits in patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC). However, the tumor may inevitably develop resistance to the targeted therapy, thereby limiting the response rate and durability. This study aimed to determine the genetic alterations associated with intrinsic and acquired resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC.MethodsTargeted sequencing of 520 cancer-related genes was performed in tumor tissues and in plasma samples collected from patients with BRAF V600E-mutant mCRC, who were treated with EGFR/BRAF ± MEK inhibitors, before and after the targeted treatment. Clinical benefit was defined as an objective response or a stable disease lasting longer than the median progression-free survival (PFS).ResultsIn all, 25 patients with BRAF V600E-mutant mCRC were included in this study. Those with RNF43 mutations (n = 8) were more likely to achieve clinical benefit from EGFR/BRAF inhibitors than those with wild-type RNF43 (87.5% versus 37.5%, p = 0.034). Genetic alterations in receptor tyrosine kinase genes (n = 6) were associated with worse PFS (p = 0.005). Among the 23 patients whose disease progressed after the EGFR/BRAF-targeted therapy, at least one acquired resistance-related mutation was detected in 12 patients. Acquired mutations were most frequently observed in the mitogen-activated protein kinase pathway-related genes (n = 9), including KRAS (G12D and Q61H/R), NRAS (Q61L/R/K and amplification), BRAF (amplification), and MEK1 (K57T). MET amplification and PIK3R1 Q579fs mutation emerged in three patients and one patient, respectively, after disease progression.ConclusionMultiple genetic alterations are associated with clinical benefits and resistance to EGFR/BRAF inhibitors in BRAF V600E-mutant mCRC. Our findings provide novel insights into strategies for overcoming resistance to EGFR/BRAF inhibitors in patients with BRAF V600E-mutant mCRC.
| S-EPMC9210093 | biostudies-literature
Project description:Colorectal cancers (CRCs) harboring the BRAF(V600E) mutation are associated with aggressive disease and resistance to BRAF inhibitors by feedback activation of the receptor tyrosine kinase (RTK)→RAS→MAPK pathway. The oncogenic MUC1-C protein promotes progression of colitis to CRC; whereas there is no known involvement of MUC1-C in BRAF(V600E) CRCs. The present work demonstrates that MUC1 expression is significantly upregulated in BRAF(V600E) vs wild-type CRCs. We show that BRAF(V600E) CRC cells are dependent on MUC1-C for proliferation and BRAF inhibitor (BRAFi) resistance. Mechanistically, MUC1-C integrates induction of MYC in driving cell cycle progression with activation of the SHP2 phosphotyrosine phosphatase, which enhances RTK-mediated RAS→ERK signaling. We demonstrate that targeting MUC1-C genetically and pharmacologically suppresses (i) activation of MYC, (ii) induction of the NOTCH1 stemness factor, and (iii) the capacity for self-renewal. We also show that MUC1-C associates with SHP2 and is required for SHP2 activation in driving BRAFi-induced feedback of ERK signaling. In this way, targeting MUC1-C in BRAFi-resistant BRAF(V600E) CRC tumors inhibits growth and sensitizes to BRAF inhibition. These findings demonstrate that MUC1-C is a target for the treatment of BRAF(V600E) CRCs and for reversing their resistance to BRAF inhibitors by suppressing the feedback MAPK pathway.
| S-EPMC10408991 | biostudies-literature
Project description:The BRAFV600E mutation is found in 8-10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.
| S-EPMC7795863 | biostudies-literature
Project description:BackgroundV600EBRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600EBRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes.MethodsData and tissue specimens from 155 V600EBRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS).ResultsCDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03-2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10-4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19-0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16-2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS.ConclusionThe present study provides new evidence on how several well-established biomarkers perform in a homogenousV600EBRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients' stratification in clinical trials and in routine clinical practice to better estimate patients' prognosis.
| S-EPMC6889398 | biostudies-literature
Project description:BackgroundBRAF-mutant metastatic colorectal cancers (mCRCs) share many clinicopathologic features with right-sided colon tumors, including frequent peritoneal involvement. Because of the poorer outcomes associated with BRAF mutations, early enrollment in clinical trials has been encouraged. However, the use of standard eligibility and assessment criteria, such as measurable disease, has anecdotally impeded patient accrual and restricted appraisal of treatment response. We investigated whether the presence of a BRAF V600E mutation is differentially associated with sites and appearance of metastatic disease in patients matched by primary tumor location.MethodsA total of 40 patients with BRAF-mutant mCRC were matched to 80 patients with BRAF wild-type mCRC by location of primary tumor (right or left colon; rectum), sex, and age. Associations between BRAF mutation status and clinicopathologic characteristics and metastatic sites were analyzed using proportion tests. Survival was summarized with Kaplan-Meier and Cox regression methods.ResultsThe distribution of primary tumor locations was: 60% right colon, 30% left colon, and 10% rectum. Compared with BRAF wild-type tumors, BRAF-mutant tumors more commonly associated with peritoneal metastases (50% vs 31%; P=.045) and ascites (50% vs 24%; P=.0038). In patients with left colon primaries, BRAF mutations were associated with more frequent ascites (58% vs 12%; P=.0038) and less frequent liver metastases (42% vs 79%; P=.024). Among patients with right colon primaries, no significant difference in sites of disease by BRAF mutation status was observed. Disease was not measurable by RECIST 1.1 in 24% of patients with right-sided primary tumors, irrespective of BRAF mutation status. In the BRAF-mutated cohort, ascites correlated unfavorably with survival (hazard ratio, 2.35; 95% CI, 1.14, 4.83; P=.02).ConclusionsGreater frequency of ascites and peritoneal metastases, which pose challenges for RECIST 1.1 interpretation of therapeutic outcomes, are seen with BRAF-mutant mCRC, even when patients are matched for primary tumor location.
| S-EPMC5551390 | biostudies-literature
Project description:BRAFV600-mutated colorectal cancer (CRC) accounts for 8% to 12% of all CRC diagnoses. These tumors are often associated with specific patient features, including right-sided primary tumor location, peritoneal and non-regional lymph node involvement, and poor prognosis. In approximately 30% of cases, a simultaneous mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype is identified. The prognostic impact of the BRAF mutation appears to be less marked in patients with MSI-H CRC than in patients with microsatellite stable (MSS) tumor. The treatment of BRAFV600-mutated CRC is still a challenge for the clinicians, mainly due to the poor survival outcomes obtained with traditional chemotherapy regimens. In recent years, two novel treatment strategies have offered remarkable changes in the treatment of this specific patient subgroup. The first approach has included targeted therapies directed against BRAF and MEK, with support from the epidermal growth factor receptor (EGFR) blockade. The second approach has included immunotherapeutic agents that have been shown to be particularly promising for patients with simultaneous dMMR/MSI-H phenotype. Here we review the clinical trials that specifically enrolled patients with BRAF-mutated CRC, from the phase I/II studies to the phase III trial BEACON CRC. We also examine the future directions towards a molecularly guided therapy for patients with BRAF-mutated CRC and the crucial role of a molecularly and clinically based algorithm in order to offer the best choice of treatment for these patients.
| S-EPMC7260582 | biostudies-literature
Project description:The discovery of activating BRAF V600E mutations in 50% of all cutaneous melanomas has revolutionized the understanding of melanoma biology and provided new strategies for the therapeutic management of this deadly disease. Highly potent small molecule inhibitors of BRAF are now showing great promise as a novel therapeutic strategy for melanomas harboring activating BRAF V600E mutations and are associated with high levels of response. This commentary article discusses the latest data on the role of mutated BRAF in the development and progression of melanoma as the basis for understanding the mechanism of action of BRAF inhibitors in the preclinical and clinical settings. We further address the issue of BRAF inhibitor resistance and outline the latest insights into the mechanisms of therapeutic escape as well as describing approaches to prevent and abrogate the onset of both intrinsic and acquired drug resistance. It is likely that our evolving understanding of melanoma genetics and signaling will allow for the further personalization of melanoma therapy with the goal of improving clinical responses.
| S-EPMC4001781 | biostudies-literature
Project description:Opinion statementThe optimal management of advanced stage BRAF-mutated melanoma is widely debated and complicated by the availability of several different regimens that significantly improve outcomes but have not been directly compared. While there are many unanswered questions relevant to this patient population, the major uncertainty in current practice is the choice between BRAF/MEK inhibitors or immunotherapy for those with previously untreated metastatic or high-risk disease. Decisions regarding first line therapy should include consideration of patient preference as well as the presence of symptomatic metastatic disease and degree of comorbidity, particularly secondary to any history of severe auto-immune disorder.BRAF/MEK inhibitors have a high response rate and rapid onset and thus can be quickly introduced when patients are symptomatic. They have also produced long-term responses in a subset of patients with more favorable prognostic indicators. In addition, impressive survival benefits have also been observed in patients with resected stage 3 disease at high risk of recurrence. On the other hand, anti-PD-1 monotherapy is associated with high rates of clinical benefit (~45% response rate in the metastatic setting) and low rates of severe toxicity. In many patients with adverse prognostic features, we use combined anti-PD-1 and anti-CTLA-4 for metastatic disease. While associated with high rates of toxicity, adverse events are largely manageable with corticosteroids and treatment cessation, in which case patients may continue to benefit even after a limited duration of treatment.Multiple treatment options exist for patients with BRAF V600 mutant melanoma. Herein, we review the clinical data for safety and efficacy of these options.
| S-EPMC10176035 | biostudies-literature
Project description:BRAF V600E-mutant colorectal cancer (CRC) is a rare subtype of colorectal cancer with poor prognosis. Compelling evidence indicates that the heparanase (HPSE) gene has multiple functions in cancer, however, its role in BRAF V600E-mutant CRC remains elusive. Differentially expressed genes between BRAF V600E-mutant and wild-type patients were explored by analyzing public data from The Cancer Genome Atlas and the Gene Expression Omnibus. Clinical samples of 172 patients with BRAF V600E-mutant CRC diagnosed at Zhongshan Hospital Fudan University were collected. Overall survival was analyzed using Kaplan-Meier curves and Cox regression models. Cell models and xenografts were utilized to investigate the effect of HPSE on tumor proliferation. HPSE was significantly highly expressed in the BRAF V600E-mutant group. High HPSE expression level was independently associated with inferior survival in the BRAF V600E-mutant cohort. HPSE knockdown impeded tumor proliferation of BRAF V600E-mutant CRC cells in vitro and in vivo. Mechanistically, HPSE silencing arrested cell cycle in G0/G1 phase by downregulating Cyclin E2 expression via the AKT/p27Kip1 pathway. These findings support a role for HPSE in promoting BRAF V600E-mutant CRC progression, which suggests it holds great promise as a prognostic biomarker and a potential therapeutic target for the aggressive CRC subtype.
| S-EPMC9492760 | biostudies-literature