Defeating drug resistance in proliferation is challenging. Here we propose unifying signaling in cell proliferation with 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 each other in resistance. Core pathways can forecast possible resistance because acquired resistance frequently occurs through alternative proliferation pathways. This concept may help predicting the efficacy of drug combinations. The selection of distinct combinations for specific mutated pathways would be guided by clinical diagnosis.
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