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Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to
Jun Zhao1, Gen Lin2, Minglei Zhuo1
1The First Department of Thoracic Oncology, Beijing University School of Oncology, Beijing Cancer Hospital, Beijing, 100142, China.
Objectives:
The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance.
Materials And Methods:
We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59-1021 cancer-related genes.
Results And Conclusion:
Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.
Insights
Genomic profiling reveals diverse resistance mechanisms to osimertinib in non-small cell lung cancer. Understanding this heterogeneity, including CTNNB1 and TP53 mutations, is key to overcoming osimertinib resistance.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Osimertinib, a third-generation EGFR TKI, shows efficacy in EGFR-mutant NSCLC.
- Response to osimertinib is variable, suggesting underlying resistance mechanisms.
- The genomic landscape may influence osimertinib efficacy and resistance.
Purpose of the Study:
- To investigate the genomic landscape associated with osimertinib resistance in NSCLC.
- To identify novel resistance mechanisms and biomarkers for osimertinib therapy.
Main Methods:
- Retrospective multicenter study of NSCLC patients resistant to osimertinib.
- Targeted next-generation sequencing (59-1021 genes) for genomic profiling.
Main Results:
- Identified EGFR-dependent resistance mutations and alternative pathway activations in 44% of patients.
- CTNNB1 gain-of-function mutations were enriched; EGFR V834L mutation identified.
- TP53 mutations were negatively correlated with osimertinib efficacy.
Conclusions:
- Osimertinib resistance is characterized by significant inter- and intra-individual genomic heterogeneity.
- CTNNB1 and TP53 mutations represent potential mechanisms of resistance.
- Further research into the genomic drivers of resistance is warranted.
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