Integrated Genomics in Oncogene-driven NSCLC With Acquired Resistance

Integrated Genomics in Oncogene-driven Non-small Cell Lung Cancer With Acquired Resistance to Tyrosine Kinase Inhibitors

Currently, tyrosine kinase inhibitor (TKI) remains the standard of care for oncogene-driven non-small cell lung cancer (NSCLC). However, almost all oncogene-driven NSCLCs would develop acquired resistance against TKI in clinical practice. Therefore, understanding the molecular mechanisms underlying the acquired resistance is a critical issue in lung cancer. Based on the literature, acquired resistance mechanism against EGFR TKI includes EGFR secondary mutation (T790M, C797X, L792X, G796X, L718Q, and exon 20 insertions), MET amplification, HER2 amplification, acquired gene fusions, and other complex alterations.

From the perspective of mutagenesis, the acquired resistance against TKI may be associated with APOBEC mutational processes, kataegis, chromothripsis, extrachromosomal DNA (ecDNA), and the interaction among them. However, still 30% to 50% of oncogene-driven NSCLCs had no identified mechanism attributed to the acquired resistance. Previous studies mostly used targeted-gene sequencing, which may overlook some structural variation and the transcriptomic dynamics. This study aims to investigate the genomic alterations, mutational processes, and the transcriptomic landscape underlying the acquired resistance using integrated genomics.

Inclusion Criteria:

1. Histologically confirmed NSCLC, with at least one of the known oncogene mutation prior to systemic treatment: EGFR exon 18-21 activating mutation, MET exon-14-skipping mutation, ERBB2 activating mutation, ALK fusion, ROS1 fusion, RET fusion, NTRK1 fusion, NTRK2 fusion, NTRK3 fusion, BRAF V600 mutation, or KRAS G12C mutation
2. Patient had received tyrosine kinase inhibitor (TKI) with progressive disease, as assessed by the treating physician
3. Had tumor tissue available for DNA extraction and sequencing.
4. Eligible for withdrawal of a blood sample for DNA extraction and sequencing.

Exclusion Criteria:

1. Patient had not received TKI or did not have documented disease progression during TKI treatment.
2. Tumor tissue was unavailable for DNA extraction or the DNA quality did not meet the sequencing requirement.