Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma.
Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma.
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DOI：
10.1158/2159-8290.cd-17-0682
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发表时间：
2018-01
期刊：
影响因子：
28.2
通讯作者：
Lo RS
中科院分区：
文献类型：
--
作者：
Hong A;Moriceau G;Sun L;Lomeli S;Piva M;Damoiseaux R;Holmen SL;Sharpless NE;Hugo W;Lo RS
对MAPK抑制剂（MAPKi）具有抗性的黑素瘤在实验性MAPKi停药后显示出适应性丧失，并且在临床上，在药物假期后可能对MAPKi疗法重新敏感。在这里，我们发现并在治疗上利用了MAPKi-抗性MUTBRAF或MUTNRAS黑色素瘤中MAPKi-成瘾的机制。在药物戒断时明显的MAPKi成瘾表型跨越短暂的细胞周期减慢到细胞死亡反应，后者需要强大的p-ERK反弹。一般来说，药物戒断诱导的p-ERK反弹上调p38-FRA 1-JUNB-CDKN 1A和下调增殖，但只有一个强大的p-ERK反弹导致DNA损伤和parthanatos相关的细胞死亡。重要的是，MAPKi戒断过程中的DNA损伤修复通过将细胞周期减速转化为半胱天冬酶依赖性细胞死亡反应或通过进一步的parthanatos相关细胞死亡来全面增强MAPKi成瘾。特别是在MEKi-抗性MUTNRAS或非典型MUTBRAF黑色素瘤中，用I型RAF抑制剂治疗增强了由MEKi-戒断引起的p-ERK反弹，从而促进了细胞死亡主导的MAPKi-成瘾表型。因此，在疾病进展时MAPKi的中断应该与增加MAPKi成瘾的特定策略相结合。
Melanoma resistant to MAPK inhibitor(s) (MAPKi) displays loss-of-fitness upon experimental MAPKi withdrawal and, clinically, may be re-sensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi-addiction in MAPKi-resistant MUTBRAF or MUTNRAS melanoma. MAPKi-addiction phenotypes evident upon drug-withdrawal spanned transient cell-cycle slowdown to cell-death responses, the latter of which required a robust p-ERK rebound. Generally, drug withdrawal-induced p-ERK rebound up-regulated p38-FRA1-JUNB-CDKN1A and down-regulated proliferation, but only a robust p-ERK rebound resulted in DNA damage and parthanatos-related cell death. Importantly, pharmacologically impairing DNA damage repair during MAPKi withdrawal augmented MAPKi-addiction across-the-board by converting a cell-cycle deceleration to a caspase-dependent cell-death response or by furthering parthanatos-related cell death. Specifically in MEKi-resistant MUTNRAS or atypical MUTBRAF melanoma, treatment with a type I RAF inhibitor intensified p-ERK rebound elicited by MEKi-withdrawal, thereby promoting a cell-death predominant MAPKi-addiction phenotype. Thus, MAPKi discontinuation upon disease progression should be coupled with specific strategies that augment MAPKi-addiction.