A new era in lung cancer targeted therapy arrived with the discovery of a subset of lung adenocarcinomas harboring activating
mutations of the epidermal growth factor receptor (EGFR), whose tyrosine kinase activity can be selectively blocked by small molecule
pharmaceuticals referred as tyrosine kinase inhibitors (TKIs). This was the starting point for a less toxic and more effective treatment
strategy for a disease that has historically presented as chemorefractory and highly lethal. In spite of this progress, only 80% of the patients
treated with this class of compounds will obtain a clinical benefit, of variable magnitude and duration, with remaining patients being
primarily refractory to the treatment. Moreover, responding tumors will eventually develop acquired resistance to TKIs and progress
to more advanced stages. In this review we summarize the current knowledge with regard to the mechanisms leading to tumor regression
and the modifiers of this primary response that determine significant variability in sensitivity of tumors harboring EGFR activating mutations,
ranging from complete remission to primary refractoriness. We also analyze the mechanisms of secondary resistance and the
strategies the scientific community is exploring in order to overcome these barriers.
Keywords: Primary resistance, secondary resistance, refractory, sensitivity, erlotinib, gefitinib, afatinib.
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