脂肪酸氧化依赖性代谢转移调节BRAF突变的黑色素瘤对MAPK抑制剂的适应性。,Clinical Cancer Research

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脂肪酸氧化依赖性代谢转移调节BRAF突变的黑色素瘤对MAPK抑制剂的适应性。
Clinical Cancer Research ( IF 10.0 ) Pub Date : 2019-08-02 , DOI: 10.1158/1078-0432.ccr-19-0253
Andrea Aloia ₁ , Daniela Müllhaupt ₁ , Christophe D Chabbert ₁ , Tanja Eberhart ₁ , Stefanie Flückiger-Mangual ₁ , Ana Vukolic ₁ , Ossia Eichhoff ₂ , Anja Irmisch ₂ , Leila T Alexander ₃ , Ernesto Scibona ₄ , Dennie T Frederick ₅ , Benchun Miao ₅ , Tian Tian ₆ , Chaoran Cheng ₆ , Lawrence N Kwong ₇ , Zhi Wei ₆ , Ryan J Sullivan ₅ , Genevieve M Boland ₈ , Meenhard Herlyn ₉ , Keith T Flaherty ₅ , Nicola Zamboni ₃ , Reinhard Dummer ₂ , Gao Zhang ₉ , Mitchell P Levesque ₂ , Wilhelm Krek ₁ , Werner J Kovacs ₁

Affiliation

目的用MAPK抑制剂（MAPKi）治疗BRAFV600E突变型黑色素瘤可导致明显的肿瘤消退，但获得性耐药普遍存在。为了了解适应MAPKi的非突变机制并确定用MAPKi治疗的黑色素瘤的新弱点，我们集中于用MAPKi治疗的初始反应阶段。实验设计通过筛选黑色素瘤细胞表面表达的蛋白质，我们将脂肪酸转运蛋白CD36鉴定为经MAPKi短期治疗后最一致的上调蛋白质。我们进一步使用体内和体外模型研究了MAPKi对脂肪酸代谢的影响，并分析了患者的治疗前和治疗中的肿瘤标本。结果用MAPKi处理的黑素瘤细胞显示CD36和PPARα介导的肉碱棕榈酰转移酶1A（CPT1A）依赖性脂肪酸氧化（FAO）水平升高。尽管CD36是适应性和耐药性阶段黑色素瘤细胞的有用标志物，但CD36的上调在功能上并未参与表征MAPKi处理的细胞的FAO变化。需要增加FAO才能使BRAFV600E突变的黑色素瘤细胞在获得耐药性之前在MAPKi诱导的代谢压力下存活。对FAO，糖酵解和MAPK的前期和伴随抑制作用在体外和体内均协同抑制肿瘤细胞的生长。结论因此，

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A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF-mutated Melanoma to MAPK Inhibitors.

PURPOSE Treatment of BRAFV600E -mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi. EXPERIMENTAL DESIGN By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients' pre- and on-treatment tumor specimens. RESULTS Melanoma cells treated with MAPKi displayed increased levels of CD36 and of PPARα-mediated and carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). While CD36 is a useful marker of melanoma cells during adaptation and drug-tolerant phases, the upregulation of CD36 is not functionally involved in FAO changes that characterize MAPKi-treated cells. Increased FAO is required for BRAFV600E -mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior to acquiring drug resistance. The upfront and concomitant inhibition of FAO, glycolysis, and MAPK synergistically inhibits tumor cell growth in vitro and in vivo. CONCLUSIONS Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAFV600E -mutant melanoma.

更新日期：2019-11-15

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