Defeating drug resistance in tumor cell proliferation is challenging. We propose that signaling in cell proliferation takes place via two core pathways, each embodying multiple alternative pathways. We consider drug resistance through an alternative proliferation pathway – within the same or within the other core pathway. Most drug combinations target only one core pathway; blocking both can restrain proliferation. We define core pathways as independent and acting similarly in cell-cycle control, which can explain why their products (e.g., ERK and YAP1) can substitute for each other in resistance. Core pathways can forecast possible resistance because acquired resistance frequently occurs through alternative proliferation pathways. This concept may help to predict the efficacy of drug combinations. The selection of distinct combinations for specific mutated pathways would be guided by clinical diagnosis.

克服肿瘤细胞增殖的耐药性具有挑战性。我们认为细胞增殖中的信号传导通过两条核心途径发生，每条途径都包含多种替代途径。我们通过替代增殖途径来考虑耐药性——在相同或其他核心途径内。大多数药物组合仅针对一种核心途径；阻断两者可以抑制扩散。我们将核心途径定义为独立的，并且在细胞周期控制中发挥相似的作用，这可以解释为什么它们的产物（例如ERK和YAP1）可以在耐药性方面相互替代。核心途径可以预测可能的耐药性，因为获得性耐药经常通过替代增殖途径发生。这个概念可能有助于预测药物组合的功效。特定突变途径的不同组合的选择将以临床诊断为指导。