Figure 4.

A schematic presentation of pathway-dependent and pathway-independent drug resistance mechanisms in cancer cells. In pathway-dependent (black) mechanisms, a possible target receptor becomes activated, either through overexpression or a secondary mutation (for instance, the kinase domain and ectodomain mutation of epidermal growth factor receptor (EGFR) or the overexpression of a truncated version of the target receptor). In addition, gain-of-function mutations in downstream components (e.g., PIK3CA, BRAF, KRAS, etc.) or loss-of-function mutations (PTEN, a well-known inhibitor of the downstream pathway) can proliferate downstream pathways. Other possible pathway-dependent molecular mechanisms include bypass activation, leading to the amplification of other isoforms. Pathway-independent (red) mechanisms generally involve epigenetic changes. The epithelial–mesenchymal transition (EMT) in cancer tissues and the tumor microenvironment plays a vital role in developing resistance against cancer treatment. (M, methylation; dM, demethylation; TKI, tyrosine kinase inhibitors; RTK, receptor tyrosine kinase).