Lung adenocarcinoma harboring concomitant SPTBN1-ALK fusion, c-Met overexpression, and HER-2 amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy
- Fei-fei Gu1,
- Yong Zhang2,
- Yang-yang Liu1,
- Xiao-hua Hong1,
- Jin-yan Liang1,
- Fan Tong1,
- Jing-song Yang†1 and
- Li Liu†1Email author
© The Author(s). 2016
Received: 24 July 2016
Accepted: 2 August 2016
Published: 5 August 2016
Crizotinib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity against mesenchymal-epithelial transition factor (MET) and anaplastic lymphoma kinase (ALK). However, the concomitant oncogenic drivers may affect the sensitivity of crizotinib. Herein, we present a 69-year-old never-smoker Chinese male with advanced lung adenocarcinoma harboring concomitant spectrin beta non-erythrocytic 1 (SPTBN1)-ALK fusion, c-Met overexpression, and human epidermal growth factor receptor-2 (HER-2) amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy. Although the patient received timely and comprehensive treatment, the overall survival was only 8 months. Therefore, c-Met overexpression, HER-2 gene amplification, and SPTBN1-ALK gene fusion can coexist in lung adenocarcinoma and may become a potential biomarker of cancer refractory to crizotinib, chemotherapy, and radiotherapy as well as of a relatively poor prognosis. In addition, the novel SPTBN1-ALK fusion gene may become a potential target for anti-tumor therapy.
To the editor
Crizotinib is a multi-targeted tyrosine kinase inhibitor (TKI) with activity against mesenchymal-epithelial transition factor (MET) and anaplastic lymphoma kinase (ALK) . Driver oncogenes are conventionally considered mutually exclusive . Here, we describe a rare case of lung adenocarcinoma harboring concomitant spectrin beta non-erythrocytic 1 (SPTBN1)-ALK fusion, c-Met overexpression, and human epidermal growth factor receptor-2 (HER-2) amplification with inherent resistance to crizotinib, chemotherapy, and radiotherapy.
The patient initially received gemcitabine plus nedaplatin for one cycle in July 2015. Subsequent treatment included palliative radiation therapy to the left ilium. Additionally, the patient was treated with crizotinib based on c-Met overexpression. However, grade 3 thrombocytopenia occurred after chemotherapy, and he recovered with recombinant human thrombopoietin. Although the symptoms decreased, first restaging CT scans (September 2, 2015) showed marked worsening disease (Additional file 1: Figure S1a).
Then, the patient received two cycles of bevacizumab-based chemotherapy with pemetrexed, cisplatin, and bevacizumab from September to October in 2015. Additionally, he received local radiotherapy at the lumbar metastases. However, lumbar MRI and CT scan of the chest and abdomen (October 2015) showed progressive disease (Additional file 1: Figure S1b).
The SPTBN1-ALK fusion gene was first identified in colorectal cancer, which was formed by the fusion of exon 7 of the SPTBN1 gene with exon 20 of the ALK gene . In this case, we first identified a novel SPTBN1-ALK fusion in lung cancer. The frequency of c-Met overexpression is 31.9 % in NSCLC, and it potentially causes intrinsic resistance to EGFR-TKIs without causing resistance to crizotinib . Nonetheless, the present patient gained inherent crizotinib resistance despite harboring both c-Met overexpression and the SPTBN1-ALK fusion gene. HER-2 is noted in 10 to 20 % of NSCLC patients  and confers relative resistance to conventional chemotherapy . The novel ALK rearrangement and interactive crosstalk between Met and HER2 may have been responsible for the failed response to crizotinib treatment. In this context, inhibition of ALK, Met, and Her-2 was required for efficient inhibition of tumor growth.
To the best of our knowledge, this is the first case of lung cancer with a novel SPTBN1-ALK fusion gene, which may become a potential target for anti-tumor therapy. This interesting case demonstrates that c-Met overexpression, HER-2 gene amplification, and SPTBN1-ALK gene fusion can coexist in lung adenocarcinoma, and their combination might be a biomarker for resistance to crizotinib, traditional chemotherapy, and radiotherapy as well as for a relatively poor prognosis. Further evidence is required to validate these preliminary data.
ALK, anaplastic lymphoma kinase; CIK, cytokine-induced killers; DC, dendritic cell; EGFR, epidermal growth factor receptor; HER-2, human epidermal growth factor receptor-2; iAPA, inhibition of antigen presentation attenuators; MET, mesenchymal-epithelial transition factor; MRI, magnetic resonance imaging; NSCLC, non-small-cell lung cancer; PET/CT, positron emission tomography-computed tomography; ROS1, repressor of silencing 1; SPTBN1, spectrin beta non-erythrocytic 1; TKI, tyrosine kinase inhibitor
This work was supported by the grant from National Natural Science Foundations of China (NO.81372260).
Availability of data and materials
All data generated or analyzed during this study are included in this published article.
LL and JSY contributed to the design of the study. YYL and JYL acquired the data. FT and XHH conducted the data analyses and interpretation. FFG and YZ were in charge of manuscript writing. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
The authors did not obtain written consent of the patient to describe his illness and publish this case report because the patient died before we started work on the case study. However, we did not use patient data that would allow identifying him.
Ethics approval and consent to participate
Ethics committee approval is not included as it is commonly accepted that case reports do not require such approval. In our work, we did not use patient data that would allow identifying him. Patient agreed to all above diagnostic tests and treatment that was used.
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- Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693–703.View ArticlePubMedPubMed CentralGoogle Scholar
- Gainor JF, Varghese AM, Ou SHI, et al. ALK rearrangements are mutually exclusive with mutations in EGFR or KRAS: an analysis of 1683 patients with non-small cell lung cancer. Clin Cancer Res. 2013;19:4273–81.View ArticlePubMedGoogle Scholar
- Ying J, Lin C, Wu J, et al. Anaplastic lymphoma kinase rearrangement in digestive tract cancer: implication for targeted therapy in Chinese population. PLoS One. 2015;10:e0144731.View ArticlePubMedPubMed CentralGoogle Scholar
- Lou NN, Yang JJ, Zhang XC, et al. Response to tyrosine kinase inhibitors in non-small-cell lung cancer with concomitant c-MET overexpression and driver genes. J Clin Oncol. 2015;33(suppl; abstr 8089):15s.Google Scholar
- Mazières J, Peters S, Lepage B, et al. Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives. J Clin Oncol. 2013;31:1997–2003.View ArticlePubMedGoogle Scholar
- Kuyama S, Hotta K, Tabata M, et al. Impact of HER2 gene and protein status on the treatment outcome of cisplatin-based chemoradiotherapy for locally advanced non-small cell lung cancer. J Thorac Oncol. 2008;3:477–82.View ArticlePubMedGoogle Scholar