Kim Sungsoo, Carvajal Richard, Kim Minah, Yang Hee Won
Department of Pathology and Cell Biology, Columbia University, New York, NY 10032, USA.
Department of Medicine, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA.
Cell Rep. 2023 Jun 27;42(6):112570. doi: 10.1016/j.celrep.2023.112570. Epub 2023 May 29.
The combination of BRAF and MEK inhibitors (BRAFi/MEKi) has shown promising response rates in treating BRAF-mutant melanoma by inhibiting ERK activation. However, treatment efficacy is limited by the emergence of drug-tolerant persister cells (persisters). Here, we show that the magnitude and duration of receptor tyrosine kinase (RTK) activation determine ERK reactivation and persister development. Our single-cell analysis reveals that only a small subset of melanoma cells exhibits effective RTK and ERK activation and develops persisters, despite uniform external stimuli. The kinetics of RTK activation directly influence ERK signaling dynamics and persister development. These initially rare persisters form major resistant clones through effective RTK-mediated ERK activation. Consequently, limiting RTK signaling suppresses ERK activation and cell proliferation in drug-resistant cells. Our findings provide non-genetic mechanistic insights into the role of heterogeneity in RTK activation kinetics in ERK reactivation and BRAFi/MEKi resistance, suggesting potential strategies for overcoming drug resistance in BRAF-mutant melanoma.
BRAF和MEK抑制剂（BRAFi/MEKi）联合使用通过抑制ERK激活，在治疗BRAF突变型黑色素瘤方面显示出有前景的缓解率。然而，治疗效果受到耐药性持久细胞（persisters）出现的限制。在此，我们表明受体酪氨酸激酶（RTK）激活的程度和持续时间决定了ERK的重新激活和持久细胞的形成。我们的单细胞分析揭示，尽管有均匀的外部刺激，但只有一小部分黑色素瘤细胞表现出有效的RTK和ERK激活并形成持久细胞。RTK激活的动力学直接影响ERK信号动态和持久细胞的形成。这些最初罕见的持久细胞通过有效的RTK介导的ERK激活形成主要的耐药克隆。因此，限制RTK信号传导可抑制耐药细胞中的ERK激活和细胞增殖。我们的研究结果为ERK重新激活和BRAFi/MEKi耐药中RTK激活动力学异质性的作用提供了非遗传机制见解，提示了克服BRAF突变型黑色素瘤耐药性的潜在策略。
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