Busch Gianna T, Boe Ryan H, Li Jingxin, Gruener Robert F, Arnett Miles J, Ravindran Pavithran T, Herlyn Meenhard, Huang R Stephanie, Raj Arjun
Department of Bioengineering, School of Engineering and Applied Sciences University of Pennsylvania, Philadelphia, PA, USA.
Genetics and Epigenetics, Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
bioRxiv. 2025 May 6:2025.04.25.650475. doi: 10.1101/2025.04.25.650475.
Resistance to targeted therapies is a significant clinical problem, but eliminating resistant cancer cells has proven difficult. One potential reason for this difficulty is heterogeneity in the resistant population: even genetically homogeneous cancer cell populations can give rise to many resistant subtypes, each potentially with specific second-line drug vulnerabilities. Using high-throughput drug screening of genetically-identical resistant clones with varying transcriptomes and morphologies, we show that each clone had a distinct drug sensitivity profile. These results suggested that there are drugs that are effective against only subsets of resistant populations but in combination eliminate a large proportion of the resistant population. Using the individual clone sensitivity profiles, we prospectively identified combinations that were highly effective at eliminating most of the resistant population. Our results demonstrate the effectiveness of "subpopulation-directed synergy", showing that considering population heterogeneity can reveal therapeutic opportunities otherwise masked by population averages, offering new strategies to combat therapy resistance.
对靶向治疗的耐药性是一个重大的临床问题，但事实证明，消除耐药癌细胞很困难。造成这种困难的一个潜在原因是耐药群体的异质性：即使是基因同质的癌细胞群体也可能产生许多耐药亚型，每个亚型可能都有特定的二线药物易感性。通过对具有不同转录组和形态的基因相同的耐药克隆进行高通量药物筛选，我们发现每个克隆都有独特的药物敏感性谱。这些结果表明，有些药物仅对耐药群体的子集有效，但联合使用时可消除很大一部分耐药群体。利用个体克隆敏感性谱，我们前瞻性地确定了在消除大部分耐药群体方面非常有效的联合用药方案。我们的结果证明了“亚群导向协同作用”的有效性，表明考虑群体异质性可以揭示被群体平均值掩盖的治疗机会，为对抗治疗耐药性提供了新策略。
