Dataset Information

Wighteone exhibits an antitumor effect against EGFR L858R/T790M mutation non-small cell lung cancer.

ABSTRACT: Non-small cell lung cancer (NSCLC) harboring activating EGFR mutations were initially treated by first-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), unfortunately, the efficacy of these drugs is limited, mostly frequent due to T790M mutation. Although osimertinib has been approved to treat patients with T790M-positive NSCLC, the majority of patients will develop C797S mutation and suffer diseases again. Therefore, more novel therapeutic strategies for T790M mutation-positive NSCLC are urgently required. We hypothesized that wighteone, a natural compound isolated from plant derivatives, has antitumor effects against NSCLC with T790M mutation. In this study, we created a Ba/F3 cell line harboring EGFR L858R/T790M mutation (Ba/F3 EGFR L858R/T790M cell line), and then used this cell line and a human NSCLC cell line with EGFR L858R/T790M mutation (NCI-H1975) to investigate the effects and mechanism of wighteone. The results showed that wighteone inhibited cell proliferation, suppressed EGFR signaling pathway, caused cell cycle redistribution and induced cell apoptosis. Our studies suggest that wighteone may provide a novel potential therapeutic strategy for NSCLC patients with T790M mutation.

SUBMITTER: Sun P

PROVIDER: S-EPMC8176237 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Activating double mutations L858R/T790M in the epidermal growth factor receptor (EGFR) region are often observed as the cause of resistance to tyrosine kinase inhibitors (TKIs). Third-generation EGFR-TKIs, such as osimertinib and rociletinib (CO-1686), was developed to target such resistance mutations. The detection of activating L858R/T790M mutations is necessary to select sensitive patients for therapy. Hence, we aimed to develop novel radiobromine-labeled CO-1686 as a positron emission tomography (PET) imaging probe for detecting EGFR L858R/T790M mutations. Nonradioactive brominated-CO1686 (BrCO1686) was synthesized by the condensation of N-(3-[{2-chloro-5-(trifluoromethyl)pyrimidin-4-yl}amino]-5-bromophenyl) acrylamide with the corresponding substituted 1-(4-[4-amino-3-methoxyphenyl]piperazine-1-yl)ethan-1-one. The radiobrominated [77Br]BrCO1686 was prepared through bromodestannylation of the corresponding tributylstannylated precursor with [77Br]bromide and N-chlorosuccinimide. Although we aimed to provide a novel PET imaging probe, 77Br was used as an alternative radionuclide for 76Br. We fundamentally evaluated the potency of [77Br]BrCO1686 as a molecular probe for detecting EGFR L858R/T790M using human non-small-cell lung cancer (NSCLC) cell lines: H1975 (EGFR L858R/T790M), H3255 (EGFR L858R), and H441 (wild-type EGFR). The BrCO1686 showed high cytotoxicity toward H1975 (IC50 0.18 ± 0.06 µM) comparable to that of CO-1686 (IC50 0.14 ± 0.05 µM). In cell uptake experiments, the level of accumulation of [77Br]BrCO1686 in H1975 was significantly higher than those in H3255 and H441 upon 4 h of incubation. The radioactivity of [77Br]BrCO1686 (136.3% dose/mg protein) was significantly reduced to 56.9% dose/mg protein by the pretreatment with an excess CO-1686. These results indicate that the binding site of the radiotracers should be identical to that of CO-1686. The in vivo accumulation of radioactivity of [77Br]BrCO1686 in H1975 tumor (4.51 ± 0.17) was higher than that in H441 tumor (3.71 ± 0.13) 1 h postinjection. Our results suggested that [77Br]BrCO1686 has specificity toward NSCLC cells with double mutations EGFR L858R/T790M compared to those in EGFR L858R and wild-type EGFR. However, the in vivo accumulation of radioactivity in the targeted tumor needs to be optimized by structural modification.

Project description:BACKGROUND:Despite the impressive anti-tumor activity of osimertinib in epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC) patients, 30-40% of patients still show limited response. There is therefore a need to identify biomarkers that accurately predict the response to osimertinib therapy. In this study, 54 patients with targeted next-generation sequencing of circulating tumor DNA before osimertinib treatment and known T790M positivity were included. We investigated the predictive value of baseline circulating tumor DNA-derived biomarkers on osimertinib therapy. RESULTS:Baseline maximum somatic allele frequency (MSAF) level was not associated with objective response rate (ORR) (P?=?0.886) and progression-free survival (PFS) (P?=?0.370) of osimertinib treatment. T790M relative mutation purity (RMP, defined here as the ratio of T790M AF to MSAF) quartiles were found to be significantly associated with ORR (P for trend?=?0.002) and PFS (P for trend?=?0.006), and a cut off value of 0.24 identified two distinct prognostic groups [Hazard ratio (HR)?=?0.36 for low T790M RMP, 95% confidence interval (CI) 0.18-0.72, P?=?0.004). Additionally, although T790M relative mutation abundance (RMA, defined as T790M AF/EGFR driver AF) quartiles were not significantly associated with ORR (P for trend?=?0.063), a cut off value of 0.30 also identified two distinct prognostic groups (HR?=?0.43 for low T790M RMA, 95% CI 0.22-0.85, P?=?0.015). However, in multivariate analysis, grouping of T790M RMP showed a better predictive value (HR?=?0.46, 95% CI 0.20-1.05, P?=?0.066) than T790M RMA (HR?=?0.71, 95% CI 0.31-1.61, P?=?0.409). Moreover, T790M RMP as continuous covariate was independently predictive of PFS (HR?=?0.15, 95% CI 0.03-0.79, P?=0.025), while T790M RMA was not (HR?=?1.14, 95% CI 0.49-2.66, P?=0.766). An external validation cohort further confirmed the T790M RMP was significantly associated with PFS of osimertinib therapy. CONCLUSIONS:This study established the independent predictive role of T790M RMP in NSCLC patients receiving osimertinib treatment.

Dataset Information

Wighteone exhibits an antitumor effect against EGFR L858R/T790M mutation non-small cell lung cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets