Stamatakos Serena, Beretta Giovanni Luca, Vergani Elisabetta, Dugo Matteo, Corno Cristina, Corna Elisabetta, Tinelli Stella, Frigerio Simona, Ciusani Emilio, Rodolfo Monica, Perego Paola, Gatti Laura
Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
Cancers (Basel). 2021 May 10;13(9):2284. doi: 10.3390/cancers13092284.
Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.
促进细胞存活的代谢变化与转移性黑色素瘤的进展以及耐药性的产生有关。在BRAF抑制剂耐药的黑色素瘤细胞中，我们探究了脂肪酸合酶（FASN）的作用，该酶参与脂质生成，在转移性黑色素瘤中过表达。在对FASN进行分子靶向以及用FASN抑制剂奥利司他处理后，显示出增强迁移和促侵袭能力的耐药黑色素瘤细胞对BRAF抑制剂PLX4032的敏感性增加。这种行为与药物组合诱导的明显凋亡和半胱天冬酶3/7激活有关。在一组六个耐药/敏感匹配细胞系以及癌症细胞系百科全书中，均发现FASN的表达与BRAF突变细胞系中的耐药性呈负相关。用U18666 A抑制二氢胆固醇还原酶24（DHCR24）在耐药细胞中也观察到了良好的药物相互作用，在靶向FASN后这种相互作用增强。两种抑制剂的联合使用在耐药细胞中与PLX4032表现出协同相互作用。总之，FASN在BRAF突变的黑色素瘤进展中起作用，从而为黑色素瘤的治疗创造了新的治疗机会。
