Fig 1.

Kinase oncogene dependence and principles of drug resistance. Tumor genetic alterations (denoted by the red star) may activate protein kinase oncogenes, which in turn dysregulate a cell signaling pathway, resulting in oncogene dependence. Such tumors often respond to treatment using pharmacologic inhibitors of the mutated kinase oncoprotein; however, resistance to such agents is common. Categories of resistance to kinase inhibitors include secondary mutation (denoted by the green star), amplification, or activation of the target kinase, or bypass of the oncogenic pathway, both leading to downstream reactivation and disease progression. Bypass mechanisms activating alternative pathways have also been described (alternate pathway, see Emerging Mechanisms of Resistance to Kinase Oncogene Inhibition). In principle, reactivation of the oncogenic pathway through additional, as yet uncharacterized mechanisms (denoted by question mark) should also confer acquired resistance to targeted therapies.