A somatic mutation of the KEAP1 gene in malignant melanoma is involved in aberrant NRF2 activation and an increase in intrinsic drug resistance

摘要

Among the several characteristics of malignant melanoma, insensitivity to anti-cancer.agents is a frequent clinical problem in the treatment of patients (Grossman and Altieri, 2001). In fact, the most commonly used chemotherapy agents cisplatin and dacarbazine for malignant melanoma elicit a response rate of only 10% (Flaherty, 2010). The small-molecule inhibitor of BRAF, vemurafenib (also known as PLX4032), elicits potent tumor regression in patients with BRAF-positive stage IV melanoma (Huang et ai, 2012), and its use is expected m patients harboring the BRA~V600E mutation (Tsai et ai, 2008). However, vemurafenib is not effective against melanomas with wild-type BRAF protein (Joseph et ai, 2010). Acral lentiginous melanoma (ALM) is one of the subtypes of cutaneous melanoma most frequent in colored races (Bradford ef ai, 2009). In fact, only about 10% of ALM cases harbor the BRAFV600E mutation, compared with over 60% of cases of superficial spreading melanoma (SSM), which is most frequent in Caucasian populations (Saldanha ef al, 2006). Because these melanomas are insensitive to BRAF inhibitors (Joseph et ai, 2010), a search for molecular targets that would enhance sensitivity to standard treatment with cisplatin or dacarbazine would seem justified.