Induction of Multiple Alternative Mitogenic Signaling Pathways Accompanies Emergence of Slowly Growing Drug-Tolerant Cancer Cells

Drug resistance continues to be a major obstacle to curing cancer. Resistance can evolve from a subpopulation of cancer cells that initially survive drug treatment and then gradually form a pool of slowly growing drug-tolerant cells. Several studies have pinpointed activation of a specific bypass pathway that appears to provide the critical therapeutic target for preventing drug tolerance. Here we take a systems-biology approach using proteomics and genomics to examine the development of drug tolerance to EGFR inhibitors in EGFR -mutant lung adenocarcinoma cells and BRAF inhibitors in BRAF -mutant melanoma cells. We found that there are numerous alternative mitogenic pathways that become activated in both cases, including YAP, STAT3, IGFR1, and phospholipase C (PLC)/protein kinase C (PKC) pathways. Our results suggest that an effective therapeutic strategy to prevent drug tolerance will need to take multiple alternative mitogenic pathways into account rather than focusing on one specific pathway.