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.
Highlights
Malignant pleural mesothelioma (MPM) is an aggressive cancer originating in the pleura
To assess the frequency of co-activation in primary mesotheliomas, we examined the co-expression of mTOR and ALK, ROS1, and MET at both mRNA and protein levels in tumor samples by qRT-PCR and IHC, respectively
Immunostaining of ALK, MET and mTOR on tissue microarrays was interpretable in 101 mesotheliomas (Table 1)
Summary
Malignant pleural mesothelioma (MPM) is an aggressive cancer originating in the pleura. MPM is associated with poor prognosis: less than 5% of patients survive more than five years [1]. Surgery combined with radio-chemotherapy has shown benefit in patients presenting with early-stage disease [2], but most MPM are in advanced stage and show multi-focal growth at the time of diagnosis. The current treatment standard for advanced MPM - chemotherapy with cisplatin and pemetrexed or raltitrexed - is effective only in 25-30% of patients, and median survival is 12 months [3]. There is no approved salvage regimen after failure of first-line chemotherapy. New drugs targeting aberrantly activated signaling molecules may be candidate therapeutics in MPM
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