Osimertinib for lung cancer cells harboring low-frequency EGFR T790M mutation

Joshi, Asim; Butle, Ashwin; Hait, Supriya; Mishra, Rohit; Trivedi, Vaishakhi; Thorat, Rahul; Choughule, Anuradha; Noronha, Vanita; Prabhash, Kumar; Dutt, Amit

doi:10.1016/j.tranon.2022.101461

Cited by 5 publications

(7 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, resistance to these molecules poses significant limitations to their use. [43] Using molecular docking technology, we studied the mechanism underlying the binding of 2b to EGFR. Table 2 lists the docking results for compound 2b and PD, respectively, with EGFR, using the LibDock tool of Discovery Studio (DS).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives of Panaxadiol

Han

Miao

et al. 2022

Chemistry & Biodiversity

View full text Add to dashboard Cite

Based on the well‐known cytotoxicity of indole compounds, we used the ‘Fisher indole synthesis’ method to introduce appropriately substituted indole rings into panaxadiol (PD), generating eighteen novel Panaxadiol indole derivatives. Six human cancer cell lines (A549, HepG‐2, HCT‐116, SGC‐7901, MDA‐MB‐231, PC‐3 cells) and one normal ovarian cell lines (IOSE144) were designed to evaluate the anti‐proliferative activity of the PD derivatives. The results showed that the majority of PD derivatives showed enhanced anti‐proliferative activity, when compared with PD, with P‐Methylindolo‐PD exhibiting the highest cytotoxicity. In A549 cells, IC50 value was 5.01±0.87 μM, which is roughly 12 times higher than the activity of PD and 5 times that of 5‐FU. Moreover, cell morphology analysis and Annexin V‐FITC/PI assays exhibited that P‐Methylindolo‐PD could induce A549 cell apoptosis (55.7 % of apoptotic cells at 20 μM). Moreover, molecular docking experiments were performed to explore the molecular mechanism underlining the binding of P‐Methylindolo‐PD to the active site of EGFR. The results support that P‐Methylindolo‐PD might be a promising lead compound for further studies.

show abstract

Section: Resultsmentioning

confidence: 99%

“…Mutations in EGFR are a major cause of non‐small cell lung cancer (NSCLC) and the specific small molecule inhibitors erlotinib and gefitinib have been developed to target EGFR. However, resistance to these molecules poses significant limitations to their use [43] …”

Section: Resultsmentioning

confidence: 99%

Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives of Panaxadiol

Han

Miao

et al. 2022

Chemistry & Biodiversity

View full text Add to dashboard Cite

show abstract

“…This disease progression is especially evident when considering mutations happening at the AF. They found that Osimertinib treatment proved advantageous for patients experiencing disease progression with the low frequency of EGFR T790M mutation . WES is a powerful tool that can be used to identify deleterious rare missense variants.…”

Section: Discussionmentioning

confidence: 99%

“…We searched the NCBI-SRA database for WES data sets of EGFR -mutated TKI resistant NSCLC samples . From PRJEB50602, we found the 16 pair-end FASTQ reads of WES data with EGFR -mutated erlotinib TKI-resistant lung adenocarcinoma tissue samples (Homo sapiens), which were processed from the Illumina HiSeq 2500 platform . These raw reads were further downloaded from the database using a sequence read archive (SRA) toolkit .…”

Section: Methodsmentioning

confidence: 99%

“… 18 From PRJEB50602, we found the 16 pair-end FASTQ reads of WES data with EGFR -mutated erlotinib TKI-resistant lung adenocarcinoma tissue samples ( Homo sapiens ), which were processed from the Illumina HiSeq 2500 platform. 19 These raw reads were further downloaded from the database using a sequence read archive (SRA) toolkit. 20 Supplementary Figure 1 depicts the entire study workflow.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Deciphering the Impact of Rare Missense Variants in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer through Whole Exome Sequencing: A Computational Approach

Balasundaram,

C Doss

2024

ACS Omega

View full text Add to dashboard Cite

Targeted therapy revolutionizes the treatment of non-small-cell lung cancer (NSCLC), harboring molecular change. Epidermal growth factor receptor(EGFR) mutations play a crucial role in the development of NSCLC, serving as a pivotal factor in its pathogenesis. We elucidated the mechanisms of resistance and potential therapeutic strategies in NSCLC resistant to the EGFRtyrosine kinase inhibitor (EGFR-TKI). This is achieved by identifying rare missense variants through whole exome sequencing (WES). The goal is to enhance our understanding, identify biomarkers, and lay the groundwork for targeted interventions, thereby offering hope for an improved NSCLC treatment landscape. We conducted WES analysis on 16 NSCLC samples with EGFR-TKIresistant NSCLC obtained from SRA-NCBI (PRJEB50602) to reveal genomic profiles within the EGFR-TKI. Our findings showed that 48% of the variants were missense, and after filtering with the Ensembl variant effect predictor, 53 rare missense variants in 23 genes were identified as highly deleterious. Further examination using pathogenic tools like PredictSNP revealed 12 deleterious rare missense variants in 7 genes: ZNF717, PSPH, ESRRA, SEMA3G, PTPN7, CAVIN4, and MYBBP1A. Molecular dynamics simulation (MDS) suggested that the L385P variant alters the structural flexibility of ESRRA, potentially leading to unfolding of ERRα proteins. This could impact their function and alter ERRα expression. These insights from MDS enhance our understanding of the structural and dynamic consequences of the L385P ESRRA variant and provide valuable implications for subsequent therapeutic considerations and targeted interventions.

show abstract

An approach for developing a blood-based screening panel for lung cancer based on clonal hematopoietic mutations

Anandakrishnan,

Shahidi,

Dai

et al. 2024

PLoS ONE

View full text Add to dashboard Cite

Early detection can significantly reduce mortality due to lung cancer. Presented here is an approach for developing a blood-based screening panel based on clonal hematopoietic mutations. Animal model studies suggest that clonal hematopoietic mutations in tumor infiltrating immune cells can modulate cancer progression, representing potential predictive biomarkers. The goal of this study was to determine if the clonal expansion of these mutations in blood samples could predict the occurrence of lung cancer. A set of 98 potentially pathogenic clonal hematopoietic mutations in tumor infiltrating immune cells were identified using sequencing data from lung cancer samples. These mutations were used as predictors to develop a logistic regression machine learning model. The model was tested on sequencing data from a separate set of 578 lung cancer and 545 non-cancer samples from 18 different cohorts. The logistic regression model correctly classified lung cancer and non-cancer blood samples with 94.12% sensitivity (95% Confidence Interval: 92.20–96.04%) and 85.96% specificity (95% Confidence Interval: 82.98–88.95%). Our results suggest that it may be possible to develop an accurate blood-based lung cancer screening panel using this approach. Unlike most other “liquid biopsies” currently under development, the approach presented here is based on standard sequencing protocols and uses a relatively small number of rationally selected mutations as predictors.

show abstract

Osimertinib for lung cancer cells harboring low-frequency EGFR T790M mutation

Cited by 5 publications

References 29 publications

Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives of Panaxadiol

Design, Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives of Panaxadiol

Deciphering the Impact of Rare Missense Variants in EGFR-TKI-Resistant Non-Small-Cell Lung Cancer through Whole Exome Sequencing: A Computational Approach

An approach for developing a blood-based screening panel for lung cancer based on clonal hematopoietic mutations

Contact Info

Product

Resources

About