KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma

Cicenas, Jonas; Tamošaitis, Linas; Kvederavičiūtė, Kotryna; Tarvydas, Ricardas; Staniute, Gintare; Kalyan, Karthik; Meškinytė-Kaušilienė, Edita; Stankevičius, Vaidotas; Valius, Mindaugas

doi:10.1007/s12032-016-0879-9

Cited by 102 publications

(91 citation statements)

References 105 publications

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“…Due to this, mutations, which cause constitutive activation of KRAS, lead to uncontrolled proliferation and other processes causing cancer development and spreading. KRAS can also regulate other signaling pathways, such as PI3K-AKT, PLC-PKC, and RAL, which are also known to be involved in cancer progression [13]. KRAS is mutated in more than 20% of human cancers, mostly in pancreatic (more than 90%), colorectal and lung cancers [13] as well as leukemias [14] (Table 1).…”

Section: Gene Mutations In Pancreatic Cancermentioning

confidence: 99%

“…KRAS can also regulate other signaling pathways, such as PI3K-AKT, PLC-PKC, and RAL, which are also known to be involved in cancer progression [13]. KRAS is mutated in more than 20% of human cancers, mostly in pancreatic (more than 90%), colorectal and lung cancers [13] as well as leukemias [14] (Table 1). Mutations of the codons G12, G13, or Q61 are usually associated with constitutively active KRAS, and recurrent mutations in K117 and A146 seem to be additional hotspots (Figure 2).…”

Section: Gene Mutations In Pancreatic Cancermentioning

confidence: 99%

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KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer

Cicenas

Kvederavičiūtė

Meskinyte³

et al. 2017

Cancers

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Pancreatic cancer is a disease that has a very high fatality rate and one of the highest mortality ratios among all major cancers, remaining the fourth leading cause of cancer-related deaths in developed countries. The major treatment of pancreatic cancer is surgery; however, only 15–20% of patients are candidates for it at the diagnosis of disease. On the other hand, survival in patients, who undergo surgery, is less than 30%. In most cancers, genome stability is disturbed and pancreatic cancer is not the exception. Approximately 97% of pancreatic cancers have gene derangements, defined by point mutations, amplifications, deletions, translocations, and inversions. This review describes the most frequent genetic alterations found in pancreatic cancer.

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Section: Gene Mutations In Pancreatic Cancermentioning

confidence: 99%

Section: Gene Mutations In Pancreatic Cancermentioning

confidence: 99%

KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer

Cicenas

Kvederavičiūtė

Meskinyte³

et al. 2017

Cancers

Self Cite

193

161

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“…Several therapies targeting BRAF are currently in use or under investigation for the treatment of BRAF-mutant metastatic melanoma, including vemurafenib [approved by the Food and Drug Administration (FDA) in 2011], dabrafenib (FDA approved in 2013), and encorafenib (FDA approval pending) [8][9][10]. More recently, BRAF inhibitors are co-administered with inhibitors of MEK, another kinase downstream of BRAF in the same signaling pathway.…”

Section: Introductionmentioning

confidence: 99%

Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study

et al. 2019

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BRAF and MEK kinase inhibitors can be highly effective in treating BRAF-mutant melanomas, but their safety and activity in patients with active/symptomatic brain metastases are unclear. We sought to shed light on this open clinical question. We conducted a multicenter retrospective study on real-life patients with melanoma and active brain metastases treated with combination BRAF/MEK inhibitors. A total of 65 patients were included (38 men and 27 women; median age: 49 years). Of them, 53 patients received dabrafenib/trametinib, 10 received vemurafenib/cobimetinib, one received encorafenib/binimetinib, and one received vemurafenib/trametinib. We did not observe any unexpected treatment-related safety signals in our cohort. Overall, 17 patients continued on therapy through the cutoff date. After initiation of therapy, steroid dose could be decreased in 22 of 33 patients (11 tapered off entirely), anticonvulsants were stopped in four of 21, and narcotics were stopped in four of 12. Median progression-free survival from the start of therapy was 5.3 months (95% confidence interval: 3.6-6.1), and median overall survival was 9.5 months (95% confidence interval: 7.7-13.5). A total of 20 patients were surviving at the cutoff date. Univariate analysis of age, sex, ulceration status, thickness, stage, location, or lactate dehydrogenase did not reveal significant predictors of progression-free survival or overall survival within our cohort, but multivariate analysis suggested that older age, lower risk location of original lesion, and nodular melanoma are poor prognostic indicators. Combination therapy with BRAF/MEK inhibitors is a viable treatment option for patients with BRAF-mutant melanoma and brain metastases, but further studies should help to define the optimal treatment approach in this population.

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“…Fig 4A illustrates the genetic interaction subnetwork that contains 82 significantly mutated network-predicted genetic interactions for SKCM and 78 known literature-derived genetic interactions connecting 84 genes (S4 Table). KRAS, encoding the human cellular homolog of a transforming gene isolated from the Kirsten rat sarcoma virus, plays essential roles in multiple cancer types, including melanoma [25,26]. Here, we identified that KRAS showed multiple significant genetic interactions with BACH2 (q = 0.005, Fig 4B), TAOK1 (q = 0.006), and NF1 (q = 0.04).…”

Section: Plos Computational Biologymentioning

confidence: 86%

Individualized genetic network analysis reveals new therapeutic vulnerabilities in 6,700 cancer genomes

et al. 2020

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Tumor-specific genomic alterations allow systematic identification of genetic interactions that promote tumorigenesis and tumor vulnerabilities, offering novel strategies for development of targeted therapies for individual patients. We develop an Individualized Network-based Co-Mutation (INCM) methodology by inspecting over 2.5 million nonsynonymous somatic mutations derived from 6,789 tumor exomes across 14 cancer types from The Cancer Genome Atlas. Our INCM analysis reveals a higher genetic interaction burden on the significantly mutated genes, experimentally validated cancer genes, chromosome regulatory factors, and DNA damage repair genes, as compared to human pan-cancer essential genes identified by CRISPR-Cas9 screenings on 324 cancer cell lines. We find that genes involved in the cancer type-specific genetic subnetworks identified by INCM are significantly enriched in established cancer pathways, and the INCM-inferred putative genetic interactions are correlated with patient survival. By analyzing drug pharmacogenomics profiles from the Genomics of Drug Sensitivity in Cancer database, we show that the network-predicted putative genetic interactions (e.g., BRCA2-TP53) are significantly correlated with sensitivity/resistance of multiple therapeutic agents. We experimentally validated that afatinib has the strongest cytotoxic activity on BT474 (IC 50 = 55.5 nM, BRCA2 and TP53 co-mutant) compared to MCF7 (IC 50 = 7.7 μM, both BRCA2 and TP53 wild type) and MDA-MB-231 (IC 50 = 7.9 μM, BRCA2 wild type but TP53 mutant). Finally, drug-target network analysis reveals several potential druggable genetic interactions by targeting tumor vulnerabilities. This study offers a powerful PLOS COMPUTATIONAL BIOLOGY

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KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma

Cited by 102 publications

References 105 publications

KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer

KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 Mutations in Pancreatic Cancer

Clinical experience with combination BRAF/MEK inhibitors for melanoma with brain metastases: a real-life multicenter study

Individualized genetic network analysis reveals new therapeutic vulnerabilities in 6,700 cancer genomes

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