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Integrative Profiling of T790M-Negative EGFR-Mutated NSCLC Reveals Pervasive Lineage Transition and Therapeutic
Khi Pin Chua1, Yvonne H F Teng2,3, Aaron C Tan2,4
1Genome Institute of Singapore, Singapore, Singapore.
Purpose:
Despite the established role of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutated NSCLC, drug resistance inevitably ensues, with a paucity of treatment options especially in EGFR T790M-negative resistance.
Experimental Design:
We performed whole-exome and transcriptome analysis of 59 patients with first- and second-generation EGFR TKI-resistant metastatic EGFR-mutated NSCLC to characterize and compare molecular alterations mediating resistance in T790M-positive (T790M+) and -negative (T790M-) disease.
Results:
Transcriptomic analysis revealed ubiquitous loss of adenocarcinoma lineage gene expression in T790M- tumors, orthogonally validated using multiplex IHC. There was enrichment of genomic features such as TP53 alterations, 3q chromosomal amplifications, whole-genome doubling and nonaging mutational signatures in T790M- tumors. Almost half of resistant tumors were further classified as immunehot, with clinical outcomes conditional on immune cell-infiltration state and T790M status. Finally, using a Bayesian statistical approach, we explored how T790M- and T790M+ disease might be predicted using comprehensive genomic and transcriptomic profiles of treatment-naïve patients.
Conclusions:
Our results illustrate the interplay between genetic alterations, cell lineage plasticity, and immune microenvironment in shaping divergent TKI resistance and outcome trajectories in EGFR-mutated NSCLC. Genomic and transcriptomic profiling may facilitate the design of bespoke therapeutic approaches tailored to a tumor's adaptive potential.
Insights
Drug resistance to EGFR TKIs in NSCLC is common. This study reveals distinct molecular changes in T790M-negative resistance, guiding future personalized treatments for EGFR-mutated lung cancer.
Area of Science:
- Oncology
- Genomics
- Translational Research
Background:
- Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors (TKIs) are standard for EGFR-mutated Non-Small Cell Lung Cancer (NSCLC).
- Acquired resistance to EGFR TKIs is a significant clinical challenge, limiting treatment options, particularly in cases lacking the T790M mutation.
Purpose of the Study:
- To comprehensively characterize and compare the molecular alterations driving resistance in EGFR-mutated NSCLC.
- To differentiate resistance mechanisms between T790M-positive (T790M+) and T790M-negative (T790M-) acquired resistance.
- To explore predictive biomarkers for T790M- and T790M+ resistance using pre-treatment genomic and transcriptomic data.
Main Methods:
- Whole-exome and transcriptome sequencing were performed on 59 patients with acquired resistance to first- and second-generation EGFR TKIs.
- Multiplex immunohistochemistry (IHC) was used for orthogonal validation of transcriptomic findings.
- Bayesian statistical modeling was employed to predict resistance profiles from treatment-naïve patient data.
Main Results:
- T790M-negative resistance was associated with a loss of adenocarcinoma lineage gene expression.
- Genomic features like TP53 alterations, 3q amplifications, and whole-genome doubling were enriched in T790M-negative tumors.
- Nearly half of resistant tumors were classified as 'immune-hot,' with outcomes influenced by immune infiltration and T790M status.
Conclusions:
- Divergent resistance trajectories in EGFR-mutated NSCLC are shaped by interactions between genetic alterations, cell plasticity, and the tumor immune microenvironment.
- Genomic and transcriptomic profiling can identify distinct resistance mechanisms.
- These insights support the development of tailored therapeutic strategies based on a tumor's adaptive potential.
