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. Overall dataset consists of 8 single-cell RNA-seq datasets generated on 10X Genomics Chromium 3' platform (two cell lines each treated with a drug for three time points and an untreated control), and 18 bulk RNA-seq datasets generated with KAPA mRNA HyperPrep Kit (two cell lines each treated with a drug for two time points plus an untreated control, with three replicates for each).