T790M Mutation Related Resistance of First Generation EGFR Inhibitors, their Treatment with Novel EGFR inhibitors in NSCLC and Their Side Effects: A Review

Abstract

The epidermal growth factor receptor (EGFR) and members of its family play a considerable role in carcinogenesis through their involvement in proliferation, apoptosis, enhanced cell motility, and neoangiogenesis.  Improper activation of EGFR TK results in increased malignant cell survival, proliferation, invasion and metastasis. EGFR overexpressions observed in tumors from more than 60% of patients with metastatic non-small-cell lungcancer (NSCLC) and are correlated with poor prognosis. The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), Gefitinib and Erlotinib, are reversible competitive inhibitors of the tyrosine kinase domain of EGFR that bind to its adenosine-5 triphosphate-binding site. Most NSCLC patients who initially respond to gefitinib and erlotinib eventually become resistant and experience progressive disease. The point mutation T790M accounts for about one half of these cases of acquired resistance. In this review, we discuss recent advances in the understanding of acquired TKI resistance in EGFR-mutant lung cancer and review therapeutic progress with second generation TKIs and combinations of targeted therapies. Various second-generation EGFR TKIs  like Neratinib, Afatinib, Tesevatinib, Dacomotinib, TAE226, AZD9291, HM61713are currently being evaluated and may have the potential to overcome T790M-mediated resistance, but these are also associated with various side effects. Overcoming of this resistance as well as discovery of new potential markers and inhibitors is the main goal of ongoing research in NSCLC.