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Ann Oncol. 2017 Oct 1;28(10):2451-2457. doi: 10.1093/annonc/mdx396.

Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).

Author information

1
Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona.
2
Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Barcelona.
3
Autonomous University of Barcelona (UAB), Barcelona.
4
Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona.
5
Single Cell Genomics Group, Centro Nacional de Análisis Genómico (CNAG) - Center for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona.
6
Pompeu Fabra University (UPF), Barcelona.
7
Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO) Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona.
8
Department of Medical Oncology, ICO, IDIBELL, L'Hospitalet, Barcelona.
9
Stem Cells and Cancer Group.
10
Molecular Oncology Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona.
11
Xenopat S.L., Business Bioincubator, Bellvitge Health Science Campus, Barcelona, Spain.

Abstract

Background:

Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance.

Methods:

For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80°C.

Results:

In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs.

Conclusion:

Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.

KEYWORDS:

EGFR; MET; NSCLC; T790M; acquired resistance; intratumor plasticity

PMID:
28961841
PMCID:
PMC5834054
DOI:
10.1093/annonc/mdx396
[Indexed for MEDLINE]
Free PMC Article

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