Abstract 1224: Combination of rapamycin and crizotinib induces partial remission of pleural mesothelioma in a patient-derived xenograft model

Abstract

Abstract Introduction: Malignant pleural mesothelioma (MPM) is a neoplasm with inferior prognosis and notorious chemotherapeutic resistance. New treatment approaches may be based on specific inhibitors against kinases that are overexpressed in MPM, such as mTOR and MET. Here we examined the tyrosine kinase ALK as a potential therapeutic target and the combinatorial efficacy of the ALK/MET inhibitor crizotinib and the mTOR inhibitor rapamycin. Methods: We investigated the ALK status and the expression of mTOR and MET in 145 primary MPM and 8 murine patient-derived xenograft models. ALK overexpression, rearrangement and mutation were studied by qRT-PCR, FISH, immunohistochemistry and sequence analysis. Expression of mTOR and MET was analyzed by qRT-PCR and immunohistochemistry. The combined anti-tumor effect of crizotinib and rapamycin was evaluated in a patient derived xenograft model. Effects of single drug vs. combination treatment on proliferation, apoptosis and autophagy were assessed using Ki-67 immunohistochemistry, TUNEL assay and LC3B immunofluorescence, respectively. Results: Overexpression of ALK transcripts was detected in 25 (19.5%) of 128 interpretable primary MPM and two xenograft tumors and was neither associated with ALK rearrangement nor with mutation of the kinase domain. ALK protein was expressed in 8.3% MPM and the two xenograft tumors expressing ALK transcript. mTOR protein expression was detected in 28.7% MPM, co-expressed with ALK and/or MET in 17.8% MPM. Applied to a patient derived MPM xenograft model that co-expressed ALK, MET and mTOR, crizotinib alone did not exert anti-tumor growth activity, but enhanced the anti-tumor effect of rapamycin: Rapamycin was effective in 3 of 5 tumors (pathological partial remission in 1, stable tumor in 2 cases). Combination treatment was active in all 5 tumors (partial remission in 4, stable tumor in 1 case). Simultaneous treatment with rapamycin and crizotinib, however, significantly suppressed tumor proliferation compared to rapamycin-single treatment. Autophagy was induced by both single drug treatments and distinctly enhanced by combination treatment, while apoptosis was not promoted. Conclusion: Dual combinatory treatment of rapamycin and crizotinib is more effective than rapamycin as single agent in suppressing MPM tumor growth and therefore merits further investigation. Citation Format: Dina Mönch, Sabine Bode-Erdmann, Jörg Kalla, Jörn Sträter, Carsten Schwänen, Roger-Fei Falkenstern-Ge, Martin Kimmich, Martin Kohlhäufl, Godehard Friedel, German Ott, Claudia Kalla. Combination of rapamycin and crizotinib induces partial remission of pleural mesothelioma in a patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1224. doi:10.1158/1538-7445.AM2017-1224