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Abstract
Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib show good response and survival benefit in EGFR-mutant lung cancer, acquired resistance inevitably develops which limits the median response duration to around 1 year. Secondary T790M gatekeeper mutation is the most common mechanism representing approximately 50% of resistance. The suggested strategies for overcoming T790M including irreversible EGFR-TKIs, mutant-selective EGFR-TKIs, EGFR dual targeting and HSP90 inhibitors should be further investigated for clinical application. Bypass signals through MET or AXL also contribute to resistance, which lead to development of MET or AXL inhibitors. Other mechanisms such as small cell transformation, epithelial-to-mesenchymal transition, PI3KCA mutation, ERK/HER2 amplification and miRNAs are other suggested candidates awaiting validation. As many resistant mechanisms have been recognized, it is important to obtain tissue samples after resistance to provide appropriate treatment. In this review, recent advances in the understanding of resistance and novel ways of overcoming it are discussed.
Figures and Tables
Fig. 1
Epidermal growth factor receptor (EGFR) tyrosine kinase mutations (reprinted from Chan SK, et al. Eur J Cancer 2006;42:17-23 (3), with permission from Elsevier).
Fig. 2
The frequency of observed drug resistance mechanisms (reprinted from Sequist LV, et al. Sci Transl Med 2011;3:75ra26 (6), with permission from American Association for the Advancement of Science). EGFR: epidermal growth factor receptor, PIK3CA: phosphatidylinositol 3 kinase catalytic subunit, SCLC: small cell lung cancer.
Fig. 3
Slow, indolent growth of lung cancer cells harboring EGFR T790M (reprinted from Oxnard GR, et al. Clin Cancer Res 2011;17:5530-5537 (8), with permission from American Association for Cancer Research).
Fig. 4
Novel mutant-selective EGFR inhibitors (Zhou W, et al. Nature 2009;462;1070-1074 (16), with permission from Nature Publishing Group).
Fig. 5
Schematic of pathways to EGFR inhibitor acquired resistance and pharmacologic approaches (Blakely CM and Bivoma TG. Cancer Discov 2012;2:872-875 (33), with permission from American Association for Cancer Research). EGFR: epidermal growth factor receptor, EMT: epithelial mesenchymal transition, ERK: extracellular signal-regulated kinase, NF-κB: nuclear factor κB, PIK3CA: phosphatidylinositol 3 kinase catalytic subunit.
Fig. 6
miRNAs associated with gefitinib resistance and EMT (Garofalo M, et al. Nat Med 2011;18:74-82 (34), with permission from Nature Publishing Group). APAF-1: apoptosis proteinase activating factor-1, EGFR: epidermal growth factor receptor, EMT: epithelial mesenchemal transition, PKC-ε: protein kinase Cε, PTEN: phosphatase and tensin homologue.
Table 2
Sensitivity of EGFR Mutation Tests
EGFR: epidermal growth factor receptor, PCR-SSCP: polymerase chain reaction-single-stranded conformation polymorphism, PCR-RFLP: polymerase chain reaction-restriction fragment length polymorphism, MALDI-TOF MS: matrix-assisted laser desorption/ionization-time of flight mass spectrometry, PNA-LNA: peptide nucleic acid-locked nucleic acid, ARMS: amplified refractory mutation system, dHPLC: denaturing high-performance liquid chromatography, SMAP: smart amplification process.
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