Clinical impact of subclonal EGFR T790M mutations in advanced-stage EGFR-mutant non-small-cell lung cancers

Autor: Paul D. Smith, Ursula Grazini, Tereza Vaclova, J. Carl Barrett, Elza C. de Bruin, Kenneth S. Thress, Aleksandra Markovets, Ryan J. Hartmaier, Lewis S. C. Ward, Daniel O'Neill, Julian Downward, Juliann Chmielecki, X. Huang
Rok vydání: 2021
Předmět:
Adult
Male
0301 basic medicine
Lung Neoplasms
Tumour heterogeneity
Class I Phosphatidylinositol 3-Kinases
Science
Mutation
Missense
Clone (cell biology)
General Physics and Astronomy
Kaplan-Meier Estimate
Article
General Biochemistry
Genetics and Molecular Biology
Circulating Tumor DNA
03 medical and health sciences
T790M
0302 clinical medicine
Epidermal growth factor
Carcinoma
Non-Small-Cell Lung
Cell Line
Tumor
Cancer genomics
Carcinoma
Humans
Medicine
Osimertinib
Lung cancer
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Aged
Retrospective Studies
Aged
80 and over
Acrylamides
Aniline Compounds
Multidisciplinary
business.industry
High-Throughput Nucleotide Sequencing
General Chemistry
Translational research
Middle Aged
medicine.disease
respiratory tract diseases
3. Good health
ErbB Receptors
030104 developmental biology
030220 oncology & carcinogenesis
Cancer research
Female
business
Zdroj: Nature Communications, Vol 12, Iss 1, Pp 1-11 (2021)
Nature Communications
ISSN: 2041-1723
Popis: Advanced non-small-cell lung cancer (NSCLC) patients with EGFR T790M-positive tumours benefit from osimertinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). Here we show that the size of the EGFR T790M-positive clone impacts response to osimertinib. T790M subclonality, as assessed by a retrospective NGS analysis of 289 baseline plasma ctDNA samples from T790M‐positive advanced NSCLC patients from the AURA3 phase III trial, is associated with shorter progression-free survival (PFS), both in the osimertinib and the chemotherapy-treated patients. Both baseline and longitudinal ctDNA profiling indicate that the T790M subclonal tumours are enriched for PIK3CA alterations, which we demonstrate to confer resistance to osimertinib in vitro that can be partially reversed by PI3K pathway inhibitors. Overall, our results elucidate the impact of tumour heterogeneity on response to osimertinib in advanced stage NSCLC patients and could help define appropriate combination therapies in these patients.
A recent clinical trial shows that a proportion of lung cancer patients carrying the EGFR T790M mutation develop resistance to osimertinib. In this study, the authors show that T790M subclonality is associated with worse clinical outcome likely through co-occurring PIK3CA alterations, which can be targeted by PI3K pathway inhibitors.
Databáze: OpenAIRE
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