Clinical significance of epidermal growth factor receptor tyrosine kinase inhibitors: Sensitivity and resistance

Gefitinib and erlotinib, which are epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs), are highly effective against lung tumors with EGFR activating mutations. However, in 20-30% of cases, there is intrinsic resistance, and even if the treatment is effective, resistance is acquired in one to several years. Possible mechanisms of acquired resistance to EGFR-TKI, thus far, include a gatekeeper mutation of EGFR, activation of an alternate pathway, activation of EGFR downstream signals, transformation to small cell lung cancer, and epithelial-mesenchymal transition (EMT). Recently, BIM (BCL2L11), which is a BH3-only proapoptotic member of the Bcl-2 protein family, was shown to play a central role in inducing apoptosis in response to EGFR-TKI treatment in EGFR mutant lung cancer cells. Moreover, when the expression of active BIM protein was low, there was resistance to apoptosis induction by EGFR-TKI treatment and early disease progression. A polymorphism of the BIM gene unique to East Asian people has been detected and is now attracting attention as a factor causing resistance to EGFR-TKI due to decreased BIM activity.