HSP90 inhibition overcomes EGFR amplification‐induced resistance to third‐generation EGFR‐TKIs

Abstract

Background Patients with non‐small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third‐generation EGFR‐TKIs overcome this resistance by selectively inhibiting EGFR with EGFR‐TKI‐sensitizing and T790M mutations, acquired resistance to third‐generation EGFR‐TKIs invariably develops. Methods Next‐generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M‐mutated NSCLC patient who had progressed after a third‐generation EGFR‐TKI, TAS‐121. EGFR‐mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR‐TKIs and a heat shock protein 90 (HSP90) inhibitor. Results NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M‐mutated cell line was sensitive to osimertinib or TAS‐121 in vitro, EGFR‐overexpressing cell lines displayed resistance to these EGFR‐TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third‐generation EGFR‐TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. Conclusions EGFR amplification confers resistance to third‐generation EGFR‐TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification‐mediated resistance.

Design, Synthesis, and Anticancer Activity of Some New N-{5-[(1H-Benzo[d]imidazol-1-yl)methyl]isoxazol-3-yl}benzamide Hybrids

“…Benzimidazole (1) was treated with 4-bromo-3oxobutanenitrile in presence of a base such as Cs 2 CO 3 in acetonitrile and gave 4-(1H-benzo[d]imidazol-1-yl)-3oxobutanenitrile (2). The obtained compound was reacted with hydroxylamine sulfate under basic conditions (pH 7-8) to produce aryl amine (3). Finally, the intermediate 3 was treated with several aromatic carboxylic acids in presence of coupling agents such as EDCI and HOBt in dichloromethane to give the corresponding amides 4a-4m with high yields (Scheme 1).…”

“…Isoxazole derivatives are used as adaptable building blocks in synthesis of anticancer agents [1]. For example, resorcinyl 4,5-diarylisoxazole amides was developed as a potent heat shock protein (HSP90) inhibitor (NVP-AUY922 (Luminespib)) [2], was active against a variety of tumor xenografts, and has been evaluated in phase II clinical trials [3]. Isoxazole derivatives of comberastatin A-4 analogues were described as tubulin polymerization inhibitors with anti-proliferative activity towards various cellines [4,5].…”

Predictive Value of Serum Heat Shock Protein 90α on the Prognosis of Patients with Lung Adenocarcinoma

“… 36 Additionally, as a class of proteins of interest and relevance to tumor growth, HSP90 has been shown in previous in vitro and vivo studies to be effective in inhibiting the proliferation of lung adenocarcinoma cells with EGFR mutations or ALK-rearranged. In the study by Piotrowska et al, 37 a total of 29 patients with EGFR-mutated lung adenocarcinoma were included, with an ORR of 17% and a median OS of 13 months after treatment with an HSP90 inhibitor. In a study by Sang et al, 38 it was first demonstrated in vitro that hsp90 inhibitors in non-adenocarcinoma cell lines with ALK rearrangement could inhibit cell proliferation in a gradient manner and that EGFR and ALK expression levels in the cell lines were subsequently reduced.…”