Elsevier

Lung Cancer

Volume 102, December 2016, Pages 118-121
Lung Cancer

Response and acquired resistance to crizotinib in Chinese patients with lung adenocarcinomas harboring MET Exon 14 splicing alternations

https://doi.org/10.1016/j.lungcan.2016.11.006Get rights and content

Highlights

  • CtDNA may serve as an alternative material for driver gene mutation analysis.

  • MET exon 14 splicing mutation was identified in a Chinese patient in ctDNA.

  • Three mutation in the MET kinase domain were related to resistance to crizotinib.

Abstract

Approximately 10% of lung adenocarcinomas harbor aberrations that are targetable using the approved multitargeted TKI crizotinib. MET exon 14 skipping mutation predicts for response to crizotinib in human lung adenocarcinomas. However, a substantial part of patients still has no sufficient tissue to perform genomic analysis. As a promising noninvasive biomarker and potential surrogate for the entire tumor genome, circulating tumor DNA (ctDNA) has been applied to the detection of driver gene mutations. Here we described the MET exon 14 splicing mutations in cell-free circulating-tumor DNA by next-generation sequencing (NGS) technology. Patient firstly responded to crizotinib therapy within four months, however, three acquired mutation in the MET kinase domain, D1228N/H and Y1230H, were found at the time of disease progression. To our knowledge, this is the first clinical report of three mutations simultaneously arising in a patient with MET exon 14 splicing mutation.

Introduction

Lung cancer is the leading cause of cancer-related death worldwide, and in recent years, we have witnessed the development of targeted therapies against many of the molecules frequently mutated in lung cancer [1]. In fact, two-thirds of lung adenocarcinoma cases harbor driving mutations that activate the receptor tyrosine kinases (for example, EGFR and less frequently, ALK, ROS1, RET, MET and HER2) and/or their downstream pathways, such molecules that play key roles in the RAS-RAF-MEK-ERK pathway and the PI3K-AKT pathway) [2], [3], [4]. Recently, advancement in next-generation sequencing (NGS) technology has greatly assisted the discovery of rarer driver mutations that may serve as potential therapeutic targets in lung cancer. MET has been identified as a novel promising target. Recently, the discovery of MET exon 14 skipping further attracts attention on MET-targeting therapies. It is reported that NSCLC patients harboring MET exon 14 mutation responded effectively to MET inhibitors such as crizotinib [5], [6], [7], [8], [9], [10], [11], [12].

Although emerging the encouraging clinical data about MET, experience on other RTK inhibitors suggests that resistance will develop despite remarkable initial responses [13], [14]. The known mechanisms of acquired resistance to kinase inhibitors can been classified into following categories: secondary mutations; gene amplification; bypass or alternative signaling activation; and histological and phenotypic transformation among others [15]. However, the prevalence of mechanisms of resistance to MET inhibitors among patients with MET exon 14 skipping remains unknown.

Through targeted NGS with a selected cancer-related gene panel, we identified one such MET exon 14 splicing mutation in a Chinese patient with lung adenocarcinoma, who responded to crizotinib. Several acquired mutations in the MET kinase domain, such as D1228N/H and Y1230H, were found at time of progression on crizotinib.

Section snippets

Case presentation

A 60-year-old Chinese woman having no-smoking history was admitted to our hospital. She was diagnosed with stage IV left lung adenocarcinoma in January 2015, with a 5.7 × 5.1 cm left pleural-based mass invading the fourth rib, left hilar lymphadenopathy, and numerous bilateral sub-centimeter pulmonary nodules, (confirmed by biopsy). Initial genotyping of his lung tumor by a mass spectrometry–based multiplex PCR assay for common lung cancer mutations, sizing assays for EGFR, and an ALK fluorescence

Discussion

We demonstrated a patient with lung adenocarcinoma and MET exon 14 splicing mutation that was responsed to crizotinib and developed acquired resistance to crizotinib. The second peripheral blood genetic testing at the time of progression showed acquired mutations in the MET kinase domain, D1228N/H and Y1230H; in addition to the original MET splice site mutation.

Somatic splicing alternations flanking exon 14 of MET occur in 4% of lung adenocarcinomas, based on recently whole exome sequencing

Conflict of interest and source funding

The authors declared no conflicts of interests.

References (23)

  • C.E. DeSantis et al.

    Cancer treatment and survivorship statistics, 2014

    CA Cancer J. Clin.

    (2014)
  • S.F. Yeung et al.

    To KF. profiling of oncogenic driver events in lung adenocarcinoma revealed MET mutation as independent prognostic factor

    J. Thorac. Oncol.

    (2015)
  • O.J. Bakker et al.

    Dutch Pancreatitis Study G. Early versus on-demand nasoenteric tube feeding in acute pancreatitis

    N. Engl. J. Med.

    (2014)
  • A.T. Shaw et al.

    Ceritinib in ALK-rearranged non-small-cell lung cancer

    N. Engl. J. Med.

    (2014)
  • X. Liu et al.

    Next-Generation sequencing of pulmonary sarcomatoid carcinoma reveals high frequency of actionable MET gene mutations

    J. Clin. Oncol.

    (2016)
  • M.M. Awad et al.

    MET exon 14 mutations in non-small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression

    J. Clin. Oncol.

    (2016)
  • R.S. Heist et al.

    MET exon 14 skipping in non-small cell lung cancer

    Oncologist

    (2016)
  • G.M. Frampton et al.

    Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors

    Cancer Discov.

    (2015)
  • R.W. Jenkins et al.

    Response to crizotinib in a patient with lung adenocarcinoma harboring a MET splice site mutation

    Clin. Lung Cancer

    (2015)
  • S.N. Waqar et al.

    MET mutation associated with responsiveness to crizotinib

    J. Thorac. Oncol.

    (2015)
  • P.K. Paik et al.

    Response to MET inhibitors in patients with stage IV lung adenocarcinomas harboring MET mutations causing exon 14 skipping

    Cancer Discov.

    (2015)
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    These authors contributed equally to this work.

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