![]() ![]() However, the high wild-type potency and accompanying toxicities associated with such activity may well limit their utility in this setting. (4) The subsequent identification of irreversible EGFR inhibitors such as dacomitinib 3 and afatinib 4 (5) (Figure 1) that inhibit both mutants described above as well as the wild type receptor potentially offers therapeutic options for T790M positive patients. (2, 3) However, emergence of resistance to these targeted therapies continues to be a cause for concern, with the T790M mutation in particular being highlighted as a key therapeutic target. (1) Inhibition of the kinase domain of EGFR and resultant oncogenic cell signaling disruption by small molecule inhibitors such as gefitinib 1 and erlotinib 2 (Figure 1) have been shown to be particularly beneficial in those patients carrying the so-called “sensitizing mutations” such as L858R and the exon-19 deletion. The role of the epidermal growth factor receptor (EGFR) in non-small-cell lung cancer is well-known, and substantial therapeutic progress in the treatment of this disease has been made over the past 10 years through the exploitation of this insight. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. In most cases, this resistance is in the form of the T790M mutation. ![]() Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. ![]()
0 Comments
Leave a Reply. |
Details
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |