“Platelet-derived growth factor receptor alpha (PDGFRA) is a target for tyrosine kinase inhibitors (TKIs)-based targeted therapy. Dysregulation of PDGFRA has been reported in many cancers. However, PDGFRA mutations in melanomas have not been well studied. We analyzed the genetic mutations of PDGFRA in Chinese melanoma patients, and determined the inhibitory potency of TKIs such as imatinib and crenolanib on mutant PDGFRA. Experimental Design: 351 melanoma tissue samples were examined for genetic mutations in exons 12, 14 and 18 of PDGFRA. Activities of mutations in response to imatinib and crenolanib were analyzed by western blotting of tyrosine-phosphorylated PDGFRA and cell proliferation assays. Results: PDGFRA mutations were observed in 4.6% (16/351) of melanomas, and these mutations were mainly detected in acral and mucosal melanomas. PDGFRA mutations appear to be mutually exclusive with KIT mutations, but may coexist with BRAF and NRAS mutations. The genetic mutations of PDGFRA were unrelated to the age, thickness and ulceration status of primary melanomas. Thirteen mutations were not reported before, and five (P577S, V658A, R841K, H845Y and G853D) of them resulted in strong autophosphorylation of PDGFRA. Crenolanib showed higher potency than imatinib in inhibiting the kinase activity of PDGFRA. Except that V658A mutation was imatinib-resistant, all the other mutations were sensitive to both imatinib and crenolanib. Conclusions: PDGFRA mutations are detected in a small population of melanoma patients. Our study suggests that melanoma patients harboring certain PDGFRA mutations may benefit from imatinib and crenolanib treatment.”
“Aberrant expression of embryonic epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) in epithelial cells triggers EMT, neoplastic transformation, stemness, and metastatic dissemination. We found that regulation and functions of EMT-TFs are different in malignant melanoma. SNAIL2 and ZEB2 transcription factors are expressed in normal melanocytes and behave as tumor-suppressor proteins by activating an MITF-dependent melanocyte differentiation program. In response to NRAS/BRAF activation, EMT-TF network undergoes a profound reorganization in favor of TWIST1 and ZEB1. This reversible switch cooperates with BRAF in promoting dedifferentiation and neoplastic transformation of melanocytes. We detected EMT-TF reprogramming in late-stage melanoma in association with enhanced phospho-ERK levels. This switch results in E-cadherin loss, enhanced invasion, and constitutes an independent factor of poor prognosis in melanoma patients.”
Among melanomas, BRAF-mutated disease gets the vast majority of attention. Fifty percent of melanomas harbor BRAF mutations, which can be targeted with BRAF inhibitors. However, despite its notoriety, BRAF is not the only important melanoma mutation.
Another melanoma-linked mutation can be found in the NRAS gene. Like BRAF mutations, NRAS mutations are ‘driver mutations’—a tumor with an NRAS mutation is dependent on the mutation for its growth and survival. Continue reading…
“The mutation load in melanoma is generally high compared to other tumor types due to extensive UV damage. Translation of exome sequencing data into clinically relevant information is therefore challenging. This study sought to characterize mutations identified in primary cutaneous melanomas and correlate these with clinico-pathologic features.”
“Amplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities…We conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations…Melanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.“