MMP-9 as a Candidate Marker of Response to BRAF Inhibitors in Melanoma Patients With BRAFV600E Mutation Detected in Circulating-Free DNA

Abstract

The BRAFV600E mutation is associated with melanoma development and its detection in circulating-free DNA cannot be observed in all melanoma patients harboring this mutation in tumor specimens. Beside the circulating-free DNA BRAFV600E mutation, other markers of therapeutic response should be identified. Matrix metalloproteinase-9 (MMP-9) could be one of them as its role as indicator of invasiveness in melanoma have been explored. In this study, MMP-9 was evaluated in melanoma cells after treatment with dabrafenib. In vitro data were validated in 26 melanoma patients, of which 14 treated with BRAF inhibitor alone and 12 treated with both BRAF and MEK inhibitors, by ELISA assay and droplet digital PCR for measuring MMP-9 serum levels and circulating-free DNA BRAFV600E mutation, respectively. Statistical analyses were performed to evaluate the prognostic significance of MMP-9, progression-free survival (PFS) and overall survival (OS) according to the BRAFV600E mutation and MMP-9 levels. The performed analyses showed that MMP-9 and pEKR1-2 were statistically down-regulated in melanoma cells after treatment with dabrafenib. Circulating-free DNA BRAFV600E mutation was detected in 11 out of 26 melanoma patients showing higher levels of MMP-9 compared to those with undetectable BRAFV600E mutation. Furthermore, higher levels of MMP-9 and circulating-free DNA BRAFV600E mutation were associated with lower PFS and OS. Finally, the monitoring of therapy showed that MMP-9 significantly decreased at T1 and T2, but not at T-last, for the patients with detectable circulating-free DNA BRAFV600E mutation. In conclusion, high levels of MMP-9 and circulating-free DNA BRAFV600E mutation are associated with poor PFS and OS. MMP-9 may represent a promising indicator of response to BRAF inhibitors in combination with the detection of BRAFV600E mutation.

IL22 drives cutaneous melanoma cell proliferation, migration and invasion through activation of miR-181/STAT3/AKT axis

“…Consistently, we observed increased expression of p-β-catenin and MMP-4 in CM cells under IL22 treatment, revealing the underlying mechanism of IL22-induced CM progression. Interestingly, although many studies have linked diverse subset of MMP to invasion of CM [40][41][42] , to our knowledge, this is the first report for the role of MMP-4 in CM progression; however, the exact molecular mechanisms implicated in it require additional mechanistic studies.…”

Association of oral dysbiosis with oral cancer development (Review)

“…Several processes including cell proliferation, angiogenesis, mutagenesis and oncogene activation may be caused or facilitated by chronic inflammatory mediators that alter the normal homeostasis of cells and tissues (82). (50) Oral rinse (51) Saliva samples (53) Oral swabs (117) Oral rinse (181)(182)(183)(184) Samples of oral tumour and precancerous leukoplakia Samples of tongue and floor SCC and normal tissues (117) Oral swabs (175) OSCC biopsies and deep- (176) epithelium swabs (180) Oral rinse Plaque biofilm samples production of these inflammatory proteins is responsible for several types of cancer and the overexpression of these proteins (especially IL-6 and MMP-9) predict for a worse prognosis and an aggressive tumor phenotype (85)(86)(87).…”

Clinical protein science in translational medicine targeting malignant melanoma

“…The inhibition of the mutated BRAF with selective inhibitors such as vemurafenib or dabrafenib has resulted in the reduction of MAPK signalling and regression of the disease. Unfortunately, most patients quickly develop resistance to drug treatment and the identification of proteins with somatic mutations that influence the development of resistance has largely remained elusive (Salemi et al 2018).…”