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Updated: Mar 19, 2026
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Heterogeneity of resistance mutations detectable by nextgeneration sequencing in TKI-treated lung adenocarcinoma
Deborah A Belchis1, Li-Hui Tseng1,2, Thomas Gniadek1
1Department of Pathology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland, USA.
Abstract:
EGFR-mutated lung adenocarcinomas routinely develop resistance to tyrosine kinase inhibitors (TKI). To better characterize the relative frequencies of the resistance mechanisms, we analyzed 48 EGFR-mutated TKI-resistant specimens from 41 patients. Next-generation sequencing of post-treatment specimens detected EGFR p.T790M in 31 (79%) of 39 patients, PIK3CA mutations in 10 (26%), EGFR p.S768_V769delinsIL in one, and KRAS p.G12C in one. Five PIK3CA mutations were outside of codons 542, 545, and 1047. Three of four pre-treatment specimens did not carry the PIK3CA mutation found in the post-treatment sample. Small cell carcinoma transformation was identified in four patients; none had p.T790M, including two where p.T790M was identified in the co-existing adenocarcinoma. In p.T790M-mutated specimens, the allele frequency was less than 5% in 24% of cases. p.T790M allele frequency was usually lower than that of the sensitizing mutation indicating that the resistance mutation was present either in a subset of cells or, if the sensitizing mutation was amplified, in a subset of the sensitizing alleles of a dominant clone. Eight patients had multiple resistance mutations, suggesting either multiple separate resistant clones or a single clone harboring multiple resistance mechanisms. PIK3CA mutations appear to be a more significant resistance mechanism than previously recognized.
Insights
EGFR-mutated lung cancer frequently develops resistance to tyrosine kinase inhibitors (TKI). PIK3CA mutations are a more significant resistance mechanism than previously understood, appearing in 26% of TKI-resistant cases.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Epidermal growth factor receptor (EGFR) mutations drive lung adenocarcinoma.
- Tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutated lung cancer.
- Acquired resistance to TKIs is a major clinical challenge.
Purpose of the Study:
- To determine the relative frequencies of resistance mechanisms in EGFR-mutated lung cancer.
- To investigate the role of PIK3CA mutations as a resistance mechanism.
- To characterize the genetic landscape of TKI resistance.
Main Methods:
- Next-generation sequencing (NGS) of 48 post-treatment specimens from 41 patients with EGFR-mutated, TKI-resistant lung cancer.
- Analysis of pre-treatment specimens for comparison.
- Identification of genetic alterations including EGFR, PIK3CA, and KRAS mutations, and small cell carcinoma transformation.
Main Results:
- EGFR p.T790M mutation detected in 79% of patients.
- PIK3CA mutations identified in 26% of patients, with some occurring outside common codons.
- Small cell carcinoma transformation observed in 4% of patients; none harbored concurrent p.T790M.
- Multiple resistance mutations were found in 8 patients, suggesting clonal heterogeneity.
- PIK3CA mutations were found to be a more significant resistance mechanism than previously recognized.
Conclusions:
- PIK3CA mutations represent a substantial mechanism of TKI resistance in EGFR-mutated lung cancer.
- The presence of multiple resistance mechanisms indicates complex evolutionary pathways.
- Further investigation into PIK3CA's role is warranted for therapeutic strategies.
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