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

Acrylamides / therapeutic use Adult Aged Aged, 80 and over Aniline Compounds / therapeutic use Carcinoma, Non-Small-Cell Lung / drug therapy Cell Line, Tumor Circulating Tumor DNA / analysis Class I Phosphatidylinositol 3-Kinases / genetics ErbB Receptors / genetics Female High-Throughput Nucleotide Sequencing / methods Humans Kaplan-Meier Estimate Lung Neoplasms / drug therapy Male Middle Aged Mutation, Missense Protein Kinase Inhibitors / therapeutic use Retrospective Studies

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
19 03 2021
Historique:
received: 17 06 2020
accepted: 23 02 2021
entrez: 20 3 2021
pubmed: 21 3 2021
medline: 7 4 2021
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-22057-8 PMID: 33741979 PMC: PMC7979775
pubmed: 33741979
doi: 10.1038/s41467-021-22057-8
pii: 10.1038/s41467-021-22057-8
pmc: PMC7979775
doi:

Substances chimiques

Acrylamides 0
Aniline Compounds 0
Circulating Tumor DNA 0
Protein Kinase Inhibitors 0
osimertinib 3C06JJ0Z2O
Class I Phosphatidylinositol 3-Kinases EC 2.7.1.137
PIK3CA protein, human EC 2.7.1.137
EGFR protein, human EC 2.7.10.1
ErbB Receptors EC 2.7.10.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

1780

Subventions

Organisme : Cancer Research UK
ID : FC001070
Pays : United Kingdom
Organisme : Wellcome Trust
ID : FC001070
Pays : United Kingdom
Organisme : Medical Research Council
ID : FC001070
Pays : United Kingdom

Références

McGranahan, N. & Swanton, C. Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168, 613–628 (2017).
pubmed: 28187284 doi: 10.1016/j.cell.2017.01.018
Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017).
pubmed: 29106415 pmcid: 5709185 doi: 10.1038/ng.3990
Oxnard, G. R. et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation. Clin. Cancer Res. 17, 1616–1622 (2011).
pubmed: 21135146 doi: 10.1158/1078-0432.CCR-10-2692
Yu, H. A. et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin. Cancer Res. 19, 2240–2247 (2013).
pubmed: 23470965 pmcid: 3630270 doi: 10.1158/1078-0432.CCR-12-2246
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011).
pubmed: 21430269 pmcid: 3132801 doi: 10.1126/scitranslmed.3002003
Wu, S. G. et al. The mechanism of acquired resistance to irreversible EGFR tyrosine kinase inhibitor-afatinib in lung adenocarcinoma patients. Oncotarget 7, 12404–12413 (2016).
pubmed: 26862733 pmcid: 4914294 doi: 10.18632/oncotarget.7189
Finlay, M. R. et al. Discovery of a potent and selective EGFR inhibitor (AZD9291) of both sensitizing and T790M resistance mutations that spares the wild type form of the receptor. J. Med. Chem. 57, 8249–8267 (2014).
pubmed: 25271963 doi: 10.1021/jm500973a
Zhai, X., Ward, R. A., Doig, P. & Argyrou, A. Insight into the therapeutic selectivity of the irreversible EGFR tyrosine kinase inhibitor osimertinib through enzyme kinetic studies. Biochemistry 59, 1428–1441 (2020).
pubmed: 32207968 doi: 10.1021/acs.biochem.0c00104
Oxnard, G. R. et al. Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non-small-cell lung cancer. J. Clin. Oncol. 34, 3375–3382 (2016).
pubmed: 27354477 pmcid: 5035123 doi: 10.1200/JCO.2016.66.7162
Piotrowska, Z. et al. Heterogeneity underlies the emergence of EGFRT790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov. 5, 713–722 (2015).
pubmed: 25934077 pmcid: 4497836 doi: 10.1158/2159-8290.CD-15-0399
Oxnard, G. R. et al. Assessment of resistance mechanisms and clinical implications in patients with EGFR T790M-positive lung cancer and acquired resistance to osimertinib. JAMA Oncol. 4, 1527–1534 (2018).
pubmed: 30073261 doi: 10.1001/jamaoncol.2018.2969
Mok, T. S. et al. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N. Engl. J. Med. 376, 629–640 (2017).
pubmed: 27959700 doi: 10.1056/NEJMoa1612674
Papadimitrakopoulou, V. A. et al. Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer. Cancer 126, 373–380 (2020).
pubmed: 31769875 doi: 10.1002/cncr.32503
Jamal-Hanjani, M. et al. Tracking the evolution of non-small-cell lung cancer. N. Engl. J. Med. 376, 2109–2121 (2017).
doi: 10.1056/NEJMoa1616288 pubmed: 28445112
Schiavon, G. et al. Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer. Sci. Transl. Med. 7, 313ra182 (2015).
pubmed: 26560360 pmcid: 4998737 doi: 10.1126/scitranslmed.aac7551
Ariyasu, R. et al. High ratio of T790M to EGFR activating mutations correlate with the osimertinib response in non-small-cell lung cancer. Lung Cancer 117, 1–6 (2018).
pubmed: 29496249 doi: 10.1016/j.lungcan.2017.12.018
Hartmaier R. J. et al. Abstract 4897: Detection of MET-mediated EGFR tyrosine kinase inhibitor (TKI) resistance in advanced non-small cell lung cancer (NSCLC): biomarker analysis of the TATTON study. Cancer Res. 79, 4897–4897 (2019).
Ryu, S. M., Hur, J. W. & Kim, K. Evolution of CRISPR towards accurate and efficient mammal genome engineering. BMB Rep. 52, 475–481 (2019).
pubmed: 31234957 pmcid: 6726207 doi: 10.5483/BMBRep.2019.52.8.149
Sarris, E. G., Saif, M. W. & Syrigos, K. N. The biological role of PI3K pathway in lung cancer. Pharmaceuticals 5, 1236–1264 (2012).
pubmed: 24281308 pmcid: 3816662 doi: 10.3390/ph5111236
Zill, O. A. et al. The landscape of actionable genomic alterations in cell-free circulating tumor DNA from 21,807 advanced cancer patients. Clin. Cancer Res. 24, 3528–3538 (2018).
pubmed: 29776953 doi: 10.1158/1078-0432.CCR-17-3837
Strickler, J. H. et al. Genomic landscape of cell-free DNA in patients with colorectal. Cancer Cancer Discov. 8, 164–173 (2018).
pubmed: 29196463 doi: 10.1158/2159-8290.CD-17-1009
Chabon, J. J. et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat. Commun. 7, 11815 (2016).
pubmed: 27283993 pmcid: 4906406 doi: 10.1038/ncomms11815
Hong, S. et al. Concomitant genetic alterations with response to treatment and epidermal growth factor receptor tyrosine kinase inhibitors in patients with EGFR-mutant advanced non-small cell lung cancer. JAMA Oncol. 4, 739–742 (2018).
pubmed: 29596544 pmcid: 5885210 doi: 10.1001/jamaoncol.2018.0049
Zhao, S. et al. Loss of T790M mutation is associated with early progression to osimertinib in Chinese patients with advanced NSCLC who are harboring EGFR T790M. Lung Cancer 128, 33–39 (2019).
pubmed: 30642450 doi: 10.1016/j.lungcan.2018.12.010
Andre, F. et al. Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1. Ann. Oncol. 32, 208–217 (2020).
Davies, B. R. et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. Mol. Cancer Ther. 11, 873–887 (2012).
pubmed: 22294718 doi: 10.1158/1535-7163.MCT-11-0824-T
Saura, C. et al. A first-in-human phase I study of the ATP-competitive AKT inhibitor ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors. Cancer Discov. 7, 102–113 (2017).
pubmed: 27872130 doi: 10.1158/2159-8290.CD-16-0512
Otsubo, K. et al. Genetic profiling of non-small cell lung cancer at development of resistance to first- or second-generation EGFR-TKIs by CAPP-seq analysis of circulating tumor DNA. Oncologist 24, 1022–1026 (2019).
pubmed: 31023862 pmcid: 6693714 doi: 10.1634/theoncologist.2019-0101
Belchis, D. A. et al. Heterogeneity of resistance mutations detectable by nextgeneration sequencing in TKI-treated lung adenocarcinoma. Oncotarget 7, 45237–45248 (2016).
pubmed: 27304188 pmcid: 5216719 doi: 10.18632/oncotarget.9931
Wu, S. G., Chang, Y. L., Yu, C. J., Yang, P. C. & Shih, J. Y. The role of PIK3CA mutations among lung adenocarcinoma patients with primary and acquired resistance to EGFR tyrosine kinase inhibition. Sci. Rep. 6, 35249 (2016).
pubmed: 27734950 pmcid: 5062358 doi: 10.1038/srep35249
Helman, E. et al. Cell-free DNA next-generation sequencing prediction of response and resistance to third-generation EGFR inhibitor. Clin. Lung Cancer 19, 518–530 e517 (2018).
pubmed: 30279111 doi: 10.1016/j.cllc.2018.07.008
Fang, W. et al. PI3K-AKT-mTOR pathway alterations in advanced NSCLC patients after progression on EGFR-TKI and clinical response to EGFR-TKI plus everolimus combination therapy. Transl. Lung Cancer Res. 9, 1258–1267 (2020).
pubmed: 32953503 pmcid: 7481581 doi: 10.21037/tlcr-20-141
Andre, F. et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N. Engl. J. Med. 380, 1929–1940 (2019).
pubmed: 31091374 doi: 10.1056/NEJMoa1813904
de Bono, J. S. et al. Randomized phase II study evaluating Akt blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin. Cancer Res. 25, 928–936 (2019).
pubmed: 30037818 doi: 10.1158/1078-0432.CCR-18-0981
Jones, R. H. et al. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial. Lancet Oncol. 21, 345–357 (2020).
pubmed: 32035020 pmcid: 7052734 doi: 10.1016/S1470-2045(19)30817-4
Ramalingam, S. S. et al. LBA50Mechanisms of acquired resistance to first-line osimertinib: preliminary data from the phase III FLAURA study. Ann. Oncol. 29, viii740 (2018).
Leonetti, A. et al. Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer. Br. J. Cancer 121, 725–737 (2019).
pubmed: 31564718 pmcid: 6889286 doi: 10.1038/s41416-019-0573-8
Lazzari, C., Gregorc, V., Karachaliou, N., Rosell, R. & Santarpia, M. Mechanisms of resistance to osimertinib. J. Thorac. Dis. 12, 2851–2858 (2020).
pubmed: 32642198 pmcid: 7330330 doi: 10.21037/jtd.2019.08.30
Papadimitrakopoulou, V. A. et al. Epidermal growth factor receptor mutation analysis in tissue and plasma from the AURA3 trial: osimertinib versus platinum-pemetrexed for T790M mutation-positive advanced non-small cell lung cancer. Cancer 126, 373–380 (2019).
Mellert, H. et al. Development and clinical utility of a blood-based test service for the rapid identification of actionable mutations in non-small cell lung carcinoma. J. Mol. Diagn. 19, 404–416 (2017).
pubmed: 28433077 doi: 10.1016/j.jmoldx.2016.11.004
Frampton, G. M. et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat. Biotechnol. 31, 1023–1031 (2013).
pubmed: 24142049 pmcid: 5710001 doi: 10.1038/nbt.2696
Cross, D. A. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov. 4, 1046–1061 (2014).
pubmed: 24893891 pmcid: 4315625 doi: 10.1158/2159-8290.CD-14-0337
Barlaam, B. et al. Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4 -triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): a potent and selective inhibitor of PI3Kalpha and PI3Kdelta for the treatment of cancers. Bioorg. Med Chem. Lett. 25, 5155–5162 (2015).
pubmed: 26475521 doi: 10.1016/j.bmcl.2015.10.002
Furet, P. et al. Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg. Med. Chem. Lett. 23, 3741–3748 (2013).
Gilday, J. P. & Moody, D. Process for the preparation of 4-(3’-chloro-4’-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy) quinazoline. International patent publication no. WO 2004/024703 A1 (2004).
de Muinck, E. J., Trosvik, P., Gilfillan, G. D., Hov, J. R. & Sundaram, A. Y. M. A novel ultra high-throughput 16S rRNA gene amplicon sequencing library preparation method for the Illumina HiSeq platform. Microbiome 5, 68 (2017).
pubmed: 28683838 pmcid: 5501495 doi: 10.1186/s40168-017-0279-1
Coelho, M. A. et al. BE-FLARE: a fluorescent reporter of base editing activity reveals editing characteristics of APOBEC3A and APOBEC3B. BMC Biol. 16, 150 (2018).
pubmed: 30593278 pmcid: 6309101 doi: 10.1186/s12915-018-0617-1
Li, H. et al. The sequence alignment/Map format and SAMtools. Bioinformatics 25, 2078–2079 (2009).
pubmed: 19505943 pmcid: 2723002 doi: 10.1093/bioinformatics/btp352

Auteurs

Tereza Vaclova (T)

Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK.

Ursula Grazini (U)

Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.

Lewis Ward (L)

Discovery Science, BioPharmaceutical R&D, AstraZeneca, Cambridge, UK.
ORCID: 0000-0002-5087-6305

Daniel O'Neill (D)

Discovery Science, BioPharmaceutical R&D, AstraZeneca, Cambridge, UK.

Aleksandra Markovets (A)

Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.

Xiangning Huang (X)

Biometrics Oncology, Oncology R&D, AstraZeneca, Cambridge, UK.

Juliann Chmielecki (J)

Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.

Ryan Hartmaier (R)

Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.

Kenneth S Thress (KS)

Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.
Global Marketing Diagnostics, Oncology Business, AstraZeneca, Gaithersburg, MD, USA.

Paul D Smith (PD)

Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK.
ORCID: 0000-0002-2812-5978

J Carl Barrett (JC)

Translational Medicine, Oncology R&D, AstraZeneca, Boston, MA, USA.

Julian Downward (J)

Oncogene Biology, Francis Crick Institute, London, UK.
ORCID: 0000-0002-2331-4729

Elza C de Bruin (EC)

Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK. elza.de-bruin@astrazeneca.com.
ORCID: 0000-0002-8996-8354

Articles similaires

Comprehensive comparative analysis and development of molecular markers for Lasianthus species based on complete chloroplast genome sequences.

Yue Zhang, Meifang Song, Deying Tang et al.
1.00
Genome, Chloroplast Phylogeny Genetic Markers Base Composition High-Throughput Nucleotide Sequencing

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Classifications MeSH

questionsmedicales.fr › Composés chimiques organiques › Acides carboxyliques › Acides acycliques › Acrylates › Acrylamides › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Composés chimiques organiques › Amines › Dérivés de l'aniline › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Tumeurs des bronches › Carcinome bronchogénique › Carcinome pulmonaire non à petites cellules › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › ADN tumoral › ADN tumoral circulant › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Phosphatidylinositol-4-phosphate 3-kinase › Phosphatidylinositol 3-kinases de classe I › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs peptidiques › Récepteur facteur croissance › Récepteurs ErbB › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Séquençage nucléotidique à haut débit › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Analyse de survie › Estimation de Kaplan-Meier › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Tumeurs de l'appareil respiratoire › Tumeurs du poumon › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation faux-sens › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéines kinases › Clinical impact of subclonal EGFR T790M...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Caractéristiques des études épidémiologiques › Études épidémiologiques › Études de cohortes › Études rétrospectives › Clinical impact of subclonal EGFR T790M...