Melanoma resistant to MAPK inhibitors (MAPKi) displays loss of fitness upon experimental MAPKi withdrawal and, clinically, may be resensitized to MAPKi therapy after a drug holiday. Here, we uncovered and therapeutically exploited the mechanisms of MAPKi addiction in MAPKi-resistant BRAF^MUT or NRAS^MUT melanoma. MAPKi-addiction phenotypes evident upon drug withdrawal spanned transient cell-cycle slowdown to cell-death responses, the latter of which required a robust phosphorylated ERK (pERK) rebound. Generally, drug withdrawal–induced pERK rebound upregulated p38–FRA1–JUNB–CDKN1A and downregulated proliferation, but only a robust pERK 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 NRAS^MUT or atypical BRAF^MUT melanoma, treatment with a type I RAF inhibitor intensified pERK 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.

Significance: Discontinuing targeted therapy may select against drug-resistant tumor clones, but drug-addiction mechanisms are ill-defined. Using melanoma resistant to but withdrawn from MAPKi, we defined a synthetic lethality between supraphysiologic levels of pERK and DNA damage. Actively promoting this synthetic lethality could rationalize sequential/rotational regimens that address evolving vulnerabilities. Cancer Discov; 8(1); 74–93. ©2017 AACR.

See related commentary by Stern, p. 20.

This article is highlighted in the In This Issue feature, p. 1

抗MAPK抑制剂（MAPKi）的黑色素瘤在实验性MAPKi撤药后表现出适应性丧失，并且在临床上可能会在放假后对MAPKi治疗重新敏感。在这里，我们发现并治疗性地利用了耐MAPKi的BRAF ^MUT或NRAS ^MUT中MAPKi成瘾的机制黑色素瘤。停药后明显的MAPKi上瘾表型跨越了短暂的细胞周期减慢至细胞死亡反应，后者需要强大的磷酸化ERK（pERK）反弹。通常，停药引起的pERK反弹会上调p38–FRA1–JUNB–CDKN1A并下调增殖，但只有强烈的pERK反弹会导致DNA损伤和与花蜜相关的细胞死亡。重要的是，在MAPKi撤药过程中，药理学上损害DNA损伤的修复可通过将细胞周期减速转变为caspase依赖性细胞死亡反应或进一步加剧与花粉病相关的细胞死亡，从而全面增加MAPKi的成瘾性。特别是在耐MEKi的NRAS ^MUT或非典型的BRAF ^MUT中黑色素瘤，用I型RAF抑制剂治疗可增强MEKi戒断引起的pERK反弹，从而促进以细胞死亡为主的MAPKi上瘾表型。因此，在疾病发展过程中终止MAPKi应与增加MAPKi成瘾性的特定策略相结合。

意义：停止靶向治疗可能会选择抗药性肿瘤克隆，但药物成瘾机制尚不清楚。使用对MAPKi具有抗药性但从MAPKi中退出的黑素瘤，我们定义了pERK的超生理水平与DNA损伤之间的合成致死性。积极促进这种综合杀伤力可以合理化解决不断发展的漏洞的顺序/轮换方案。巨蟹座Discov; 8（1）；74–93。©2017 AACR。

参见Stern，p。的相关评论。20。

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