Figure 3. Models of secondary resistance.

• A. When the addictive oncoprotein is inhibited, viability is seriously compromised and cancer cells stop proliferating or die (middle). Addiction to a certain oncogene might not be a homogeneous characteristic of the cancer cell population, and drug-insensitive subclones (top and bottom) may co-exist with sensitive cells.
• B, C. Fuelled by genomic instability, targeted treatment of addicted cells may result in induction (arrows, solid line) of secondary resistance through either mutation (star) or amplification/overexpression of relevant signalling nodes. This may happen in a vertical fashion, by alterations involving downstream effectors of the original addictive pathway (B), or in a horizontal fashion, when a parallel signalling axis surrogates target blockade (C). If resistant clones are already present at the beginning of treatment (panel A), these may be selected by drug exposure (arrows, dashed line) until they outcompete sensitive cells, resulting in ‘acquired’ resistance as well.