Massive parallel sequencing and digital gene expression analysis reveals potential mechanisms to overcome therapy resistance in pulmonary neuroendocrine tumors

Robert Fred Henry Walter^1,2, Claudia Vollbrecht³, Daniel Christoph⁴, Robert Werner⁵, Jan Schmeller², Elena Flom^1,2, Georgia Trakada⁶, Aggeliki Rapti⁷, Vasilis Adamidis⁸, Wolfgang Hohenforst-Schmidt⁹, Jens Kollmeier⁵, Thomas Mairinger⁵, Jeremias Wohlschlaeger², Paul Zarogoulidis^8✉, Konstantinos Porpodis⁸, Kurt Werner Schmid², Fabian Dominik Mairinger²

1. Ruhrlandklinik, West German Lung Center, University Hospital Essen, University of Duisburg-Essen.
2. Institute of Pathology, University Hospital Essen, University of Duisburg-Essen.
3. Institute of Pathology, Charité Universitaetsmedizin, Berlin.
4. Department of Oncology, University Hospital Essen, University of Duisburg-Essen.
5. Institute of Pathology, Helios Klinikum Emil von Behring, Berlin.
6. Division of Pulmonology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra Hospital, Athens, Greece.
7. 2nd Department of Pulmonary Medicine, "Sotiria" Hospital of Chest Diseases, Athens, Greece.
8. Pulmonary Department-Oncology Unit, "G. Papanikolaou" General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.
9. Medical Clinic I,''Fuerth'' Hospital, University of Erlangen, Fuerth, Germany.

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Citation:
Walter RFH, Vollbrecht C, Christoph D, Werner R, Schmeller J, Flom E, Trakada G, Rapti A, Adamidis V, Hohenforst-Schmidt W, Kollmeier J, Mairinger T, Wohlschlaeger J, Zarogoulidis P, Porpodis K, Schmid KW, Mairinger FD. Massive parallel sequencing and digital gene expression analysis reveals potential mechanisms to overcome therapy resistance in pulmonary neuroendocrine tumors. J Cancer 2016; 7(15):2165-2172. doi:10.7150/jca.16925. Available from https://www.jcancer.org/v07p2165.htm

Abstract

Background: Lung cancer is the leading cause of cancer-related deaths worldwide. 25% show neuroendocrine differentiation (typical/atypical carcinoids, large-/small-cell neuroendocrine carcinomas). Carcinoids present with long survival rates, but metastatic carcinoids correlate with decreased survival and are commonly insensitive to standard chemotherapy or radiation. Therefore, novel therapeutic strategies are urgently needed.

Material and methods: 70 representative tumor specimens were used for next-generation sequencing analysis of 14 genes related to therapy response. Additionally, mRNA-expression profiles of 60 matching samples were determined for 13 selected drug targets by using the NanoString nCounter technology.

Results: A number of features known to sensitize tumors for different targeted therapies could be identified, which hopefully improve the clinical management of this subgroup of lung neoplasias. In particular, EGFR expression was observed in the investigated tumors in a noteworthy manner. Additionally, MDM2 was strongly expressed in the majority of all samples whereas the expression of its physiological inhibitor, CDKN2A, was nearly absent in all low-grade tumors. TP53 showed a high frequency of variants in high-grade tumors but mutations were rare in carcinoids.

Conclusion: Based on our results, therapeutic approaches with MDM2-inhibitors and monoclonal anti-EGFR antibodies may be promising in pulmonary carcinoid tumors.

Keywords: NanoString, next-generation sequencing, biomarkers, personalized therapy, lung cancer.