A New View of Pathway-Driven Drug Resistance in Tumor Proliferation

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.