Identification of MET and SRC Activation in Melanoma Cell Lines Showing Primary Resistance to PLX4032

Vergani, Elisabetta; Vallacchi, Viviana; Frigerio, Simona; Deho, Paola; Mondellini, Piera; Perego, Paola; Cassinelli, Giuliana; Lanzi, Cinzia; Testi, Maria Adele; Rivoltini, Licia; Bongarzone, Italia; Rodolfo, Monica

doi:10.1593/neo.111102

Cited by 91 publications

(96 citation statements)

References 47 publications

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“…Several mechanisms of acquired resistance to vemurafenib have been identified and these include secondary NRAS mutations (10), mutations in ARAF and CRAF (11), amplification of BRAF (12), activation of other prosurvival signaling pathways, including the phosphoinositide-3-kinase (PI3K) pathway (11), and amplification of upstream receptor tyrosine kinases such as MET (13). To date, over a dozen acquired mechanisms of resistance are described and, often, multiple mechanisms of resistance are identified in the same patient (12,14,15).…”

Section: Brafmentioning

confidence: 99%

BRAF Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in BRAFV600E Mutant Melanoma

Kulkarni

Al-Hraishawi

Simhadri

et al. 2017

Clinical Cancer Research

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Purpose: Many patients with BRAF V600E mutant melanoma treated with BRAF inhibitors experience a rapid response, but ultimately develop resistance. Insight into the mechanism of resistance is critical for development of more effective treatment strategies.Experimental Design: Comprehensive genomic profiling of serial biopsies was performed in a patient with a BRAF V600E mutant metastatic melanoma who developed resistance to vemurafenib. An AGAP3-BRAF fusion gene, identified in the vemurafenib-resistant tumor, was expressed in BRAF V600E melanoma cell lines, and its effect on drug sensitivity was evaluated.Results: Clinical resistance to vemurafenib in a melanoma harboring a BRAF V600E mutation was associated with acquisition of an AGAP3-BRAF fusion gene. Expression of the AGAP3-BRAF fusion in BRAF V600E mutant melanoma cells induced vemurafenib resistance; however, these cells remained relatively sensitive to MEK inhibitors. The patient experienced clinical benefit following treatment with the combination of a BRAF and a MEK inhibitor. Rebiopsy of the tumor at a later time point, after BRAF and MEK inhibitors had been discontinued, showed loss of the AGAP3-BRAF fusion gene. Mixing experiments suggest that cells harboring both BRAF V600E and AGAP3-BRAF only have a fitness advantage over parental BRAF V600E cells during active treatment with a BRAF inhibitor.Conclusions: We report acquisition of a BRAF fusion as a novel mechanism of acquired resistance to vemurafenib in a patient with melanoma harboring a BRAF V600E mutation. The acquisition and regression of clones harboring this fusion during the presence and absence of a BRAF inhibitor are consistent with rapidly evolving clonal dynamics in melanoma.

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Section: Brafmentioning

confidence: 99%

BRAF Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in BRAFV600E Mutant Melanoma

Kulkarni

Al-Hraishawi

Simhadri

et al. 2017

Clinical Cancer Research

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“…Emerging evidence from both preclinical studies and analysis of pre-and on-treatment biopsies from patients treated with BRAFi suggest that PTEN loss, elevated pretreatment levels of CRAF, CCND1 amplification (with consequent cyclin D1 overexpression), CDK4-activating mutations, the receptor tyrosine kinase CMET expression and tumor microenvironment hepatocyte growth factor expression (the ligand for CMET) are promising predictive biomarkers that identify relative resistance to BRAF inhibitors and are worthy of validation. 63,[70][71][72][73] Cyclin D and CDK4 alterations, PTEN loss, and hepatocyte growth factor expression all represent potential therapeutic opportunites given the emergence of selective CDK4/6 inhibitors (targeting Cyclin D and CDK4 alterations), PI3K inhibitors (PTEN loss), and anti-hepatocyte growth factor antibodies and/or CMET inhibitors (hepatocyte growth factor expression) that could be plausibly combined with BRAF inhibitors.…”

Section: Mek Inhibitorsmentioning

confidence: 99%

MAP kinase signaling and inhibition in melanoma

2012

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The mitogen-activated protein kinase (MAPK) pathway is critical to oncogenic signaling in the majority of patients with malignant melanoma. Driver mutations in both NRAS and BRAF have important implications for prognosis and treatment. The development of inhibitors to mediators of the MAPK pathway, including those to CRAF, BRAF, and MEK, has led to major advances in the treatment of patients with melanoma. In particular, the selective BRAF inhibitor vemurafenib has been shown to improve overall survival in patients with tumors harboring BRAF mutations. However, the duration of benefit is limited in many patients and highlights the need for understanding the limitations of therapy in order to devise more effective strategies. MEK inhibitors have proven to particularly active in BRAF mutant melanomas also. Emerging knowledge about mechanisms of resistance as well as a more complete understanding of the biology of MAPK pathway signaling provides insight into rational combination regimens and sequences of molecularly targeted therapies.

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“…However, the abovedescribed mutations have all been identified previously in melanoma [32,33]. Moreover, MET amplification occurs in melanoma tissues [34]; in melanoma cells, MET activation by amplification led to primary resistance to vemurafenib treatment [35]. In addition, it has been shown that hepatocyte growth factor, the only known natural ligand for MET, can cause resistance to RAF inhibitors [36,37].…”

Section: Discussionmentioning

confidence: 99%

High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients

et al. 2015

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Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.

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Identification of MET and SRC Activation in Melanoma Cell Lines Showing Primary Resistance to PLX4032

Cited by 91 publications

References 47 publications

BRAF Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in BRAFV600E Mutant Melanoma

BRAF Fusion as a Novel Mechanism of Acquired Resistance to Vemurafenib in BRAFV600E Mutant Melanoma

MAP kinase signaling and inhibition in melanoma

High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients

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