Non-genetic rewiring of ERBB signaling in cancer drug tolerance

Abstract

ERBB receptors are transmembrane receptor tyrosine kinases (RTKs) that are activated by dimerization and intracellular tyrosine phosphorylation upon ligand binding. The ERBB family includes EGFR, ERBB2, ERBB3, and ERBB4 which activate several growth and survival stimulating pathways. These signaling features of the ERBB receptors make them also potent oncogenes. Many cancer drugs targeting RTKs are in clinical use, including antibodies and small molecule inhibitors. However, despite RTK-targeted therapies often resulting in excellent initial responses in patients, drug resistance has surfaced as a hindrance blocking the long-term efficacy of these treatments. Whereas most of the cancer cells can be eradicated with RTK-targeted treatment, some cells that have or adopt special characteristics under therapy survive in the patient. These cells, called drug-tolerant persister cells (DTPs), persist in a non- or slow-cycling, dormant state. Clinically, this phenomenon is observed as a minimal residual disease (MRD). Over time, through genetic or epigenetic mechanisms, DTPs can escape dormancy which leads to relapse and the establishment of drug resistance. In this thesis, the aim was to assess the induction of ERBB receptor and -ligand expression as an adaptive tolerance mechanism upon targeted therapy, following a hypothesis that autocrine ERBB activation could be a factor in the establishment of MRD. We studied five oncogene-addicted cell lines in three treatment time points and used qPCR and western blotting methods to detect differences in the expression of ERBB receptors and their ligands. An increase upon treatment was observed in the expression of neuregulin receptors (ERBB2, ERBB3 and ERBB4), which could suggest activation of an alternative ERBB expression system upon drug treatment through increased expression of the receptor as well as autocrine expression of receptor-specific ligands. These observations with further studies could increase our understanding of the non-genetic cellular rewiring events linked to cancer drug tolerance and the characteristics of persister cells.