Met in lung cancer

Receptor tyrosine kinases play important roles in the biology of many tumor cell types. In approximately 10% of non-small cell lung cancer (NSCLC) patients mutational activation of the epidermal growth factor receptor (EGFR) results in tumor cells that are exquisitely addicted to signaling by this receptor.(1) Thus expression of mutant active EGFR but in general not wild-type EGFR predisposes NSCLC cells to inhibitors of EGFR/ErbB2. Use of EGFR inhibitory agents such as gefitinib for this subset of NSCLC patients causes tumor regression and disease stabilization for 12–18 mo, after which tumor cells become resistant to the drug.(2) Initial studies identified a second mutation within the EGFR, which results in the resistance of the tyrosine kinase to gefitinib, as a major cause of reduced tumor control.(3) This has resulted in the development of newer EGFR inhibitors, e.g., afatinib, which inhibited double mutant EGFR.(4) In a subset of these patients, however, resistance to gefitinib was not associated with EGFR mutations.(5) Clearly, other mechanisms of gefitinib resistance must be at play.