Therapy resistance arises from heterogeneous drug-tolerant persister cells or minimal residual disease (MRD) through genetic and nongenetic mechanisms. A key question is whether specific molecular features of the MRD ecosystem determine which of these two distinct trajectories will eventually prevail. We show that, in melanoma exposed to mitogen-activated protein kinase therapeutics, emergence of a transient neural crest stem cell (NCSC) population in MRD concurs with the development of nongenetic resistance. This increase relies on a glial cell line-derived neurotrophic factor-dependent signaling cascade, which activates the AKT survival pathway in a focal adhesion kinase (FAK)-dependent manner. Ablation of the NCSC population through FAK inhibition delays relapse in patient-derived tumor xenografts. Strikingly, all tumors that ultimately escape this treatment exhibit resistance-conferring genetic alterations and increased sensitivity to extracellular signal-regulated kinase inhibition. These findings identify an approach that abrogates the nongenetic resistance trajectory in melanoma and demonstrate that the cellular composition of MRD deterministically imposes distinct drug resistance evolutionary paths.

通过遗传和非遗传机制，治疗耐药性来自异质耐药持久细胞或微小残留病 (MRD)。一个关键问题是，MRD 生态系统的特定分子特征是否决定了这两种不同轨迹中的哪一种最终会占上风。我们表明，在暴露于有丝分裂原活化蛋白激酶治疗剂的黑色素瘤中，MRD 中瞬时神经嵴干细胞 (NCSC) 群的出现与非遗传抗性的发展一致。这种增加依赖于神经胶质细胞系衍生的神经营养因子依赖性信号级联，它以粘着斑激酶 (FAK) 依赖性方式激活 AKT 存活途径。通过 FAK 抑制消融 NCSC 群体可延缓患者来源的肿瘤异种移植物的复发。引人注目的是，所有最终逃脱这种治疗的肿瘤都表现出赋予耐药性的基因改变和对细胞外信号调节激酶抑制的敏感性增加。这些发现确定了一种消除黑色素瘤非遗传耐药性轨迹的方法，并证明 MRD 的细胞组成确定性地强加了不同的耐药性进化路径。