Oncotarget

Research Papers:

A subgroup of pleural mesothelioma expresses ALK protein and may be targetable by combined rapamycin and crizotinib therapy

Dina Mönch, Sabine Bode-Erdmann, Jörg Kalla, Jörn Sträter, Carsten Schwänen, Roger Falkenstern-Ge, Siegfried Klumpp, Godehard Friedel, German Ott and Claudia Kalla _

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Oncotarget. 2018; 9:20781-20794. https://doi.org/10.18632/oncotarget.25111

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Abstract

Dina Mönch1,2,3, Sabine Bode-Erdmann1,2, Jörg Kalla4, Jörn Sträter5, Carsten Schwänen6, Roger Falkenstern-Ge7, Siegfried Klumpp8, Godehard Friedel7, German Ott1,2 and Claudia Kalla1,2,3

1Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany

2Department of Clinical Pathology, Robert-Bosch-Krankenhaus, 70376 Stuttgart, Germany

3University of Tübingen, 72074 Tübingen, Germany

4Institute of Pathology, Schwarzwald-Baar-Klinikum, 78052 Villingen-Schwenningen, Germany

5Institute of Pathology, 73730 Esslingen, Germany

6Clinic of Internal Medicine, Oncology/Hematology, Gastroenterology and Infectiology, Klinikum Esslingen, 73730 Esslingen, Germany

7Center for Pulmonology and Thoracic Surgery, Klinik Schillerhöhe, 70839 Stuttgart-Gerlingen, Germany

8Hospital Pharmacy, Robert-Bosch-Krankenhaus, 70376 Stuttgart, Germany

Correspondence to:

Claudia Kalla, email: claudia.kalla@ikp-stuttgart.de

Keywords: pleural mesothelioma; ALK; crizotinib; rapamycin; combination therapy

Received: November 26, 2017    Accepted: March 12, 2018    Published: April 17, 2018

ABSTRACT

Malignant pleural mesothelioma (MPM) is a neoplasm with inferior prognosis and notorious chemotherapeutic resistance. Targeting aberrantly overexpressed kinases to cure MPM is a promising therapeutic strategy. Here, we examined ALK, MET and mTOR as potential therapeutic targets and determined the combinatorial efficacy of ALK and mTOR targeting on tumor cell growth in vivo.

First, ALK overexpression, rearrangement and mutation were studied in primary MPM by qRT-PCR, FISH, immunohistochemistry and sequence analysis; mTOR and MET expression by qRT-PCR and immunohistochemistry. Overexpression of full-length ALK transcripts was observed in 25 (19.5%) of 128 primary MPM, of which ten expressed ALK protein. ALK overexpression was not associated with gene rearrangement, amplification or kinase-domain mutation. mTOR protein was detected in 28.7% MPM, co-expressed with ALK or MET in 5% and 15% MPM, respectively. The ALK/MET inhibitor crizotinib enhanced the anti-tumor effect of the mTOR-inhibitor rapamycin in a patient-derived MPM xenograft with co-activated ALK/mTOR: combined therapy achieved tumor shrinkage in 4/5 tumors and growth stagnation in one tumor. Treatment effects on proliferation, apoptosis, autophagy and pathway signaling were assessed using Ki-67 immunohistochemistry, TUNEL assay, LC3B immunofluorescence, and immunoblotting. Co-treatment significantly suppressed cell proliferation and induced autophagy and caspase-independent, necrotic cell death. Rapamycin/crizotinib simultaneously inhibited mTORC1 (evidenced by S6 kinase and RPS6 dephosphorylation) and ALK signaling (ALK, AKT, STAT3 dephosphorylation), and crizotinib suppressed the adverse AKT activation induced by rapamycin.

In conclusion, co-treatment with rapamycin and crizotinib is effective in suppressing MPM tumor growth and should be further explored as a therapeutic alternative in mesothelioma.


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