Fig 1.

Comparison of the number and distribution of secondary resistance mutations in the tyrosine kinase domains of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). In EGFR-positive patients with acquired tyrosine kinase inhibitor (TKI) resistance, four different second-site mutations in EGFR have been identified in clinical specimens. The gatekeeper mutation T790M (bold) is the most common, present in approximately 50% of patients at the time of resistance. The remaining EGFR secondary mutations are present at low frequencies. In contrast, seven different secondary mutations have been identified in ALK-positive patients at the time of TKI resistance, including the L1196M gatekeeper mutation (bold). Despite this wider distribution of secondary mutations within the ALK tyrosine kinase domain, such mutations are found in only approximately 30% of patients.