Abstract
Abstract Malignant pleural mesothelioma (MPM) is an aggressive tumor in the lining of the lung often caused by asbestos exposure. With a median survival on standard of care chemotherapy of only 12 months from diagnosis, new therapeutic modalities and predictive biomarkers are urgently needed for MPM patients. The Neurofibromatosis 2 (NF2) tumor suppressor gene that encodes the protein merlin is disrupted in approximately 50% of MPMs. The role of merlin in cell adhesion, invasion and cell motility may be partially mediated through the focal adhesion kinase (FAK), an important signaling node downstream of integrin cell adhesion proteins. An examination of 15 mesothelioma cell lines grown in 3-dimensional Matrigel culture demonstrates that low merlin by immunoblotting correlated with increased sensitivity to the FAK inhibitor, defactinib (VS-6063). An immunohistochemistry (IHC) test for merlin may be an optimal clinical tumor specimen measurement for merlin loss, provided that merlin reduction or loss is correlated with other indicators of NF2 change. The presence or absence of merlin and NF2 was evaluated using MPM patient-derived xenograft (PDX) tumor models using merlin IHC and an NF2 Fluorescence In situ Hybridization (FISH), as well as Western blotting to determine merlin levels in the tumor lysates. The PDX MPM-0235 tumor had low merlin by Western blotting, merlin IHC, and NF2 FISH, whereas PDX MPM-0237 showed high merlin levels by Western blotting, merlin IHC, and diploid chromosome 22 by FISH. In addition to PDX analysis, Merlin IHC and NF2 FISH optimized by these conditions was evaluated with in patient MPM Tissue Microarrays (TMAs) of 64 primary tumors. Chromosome 22 monosomy was significantly more frequent than NF2 regional deletion of chromosome 22. We observed that 42% of the tumors had a low merlin IHC score (merlin-low) that correlated with loss of NF2 (unpaired t-test, p<0.029). In a second cohort of archived tumor specimens from 300 MPM patients treated at one clinical site, we observed a similar association between NF2 loss/deletion by FISH and merlin-low IHC (unpaired t-test, p=0.0001). While phosphoFAK Y397 IHC (an indicator of FAK activation) have high IHC values in some tumors that are merlin-low, these two marker trends were not statistically associated for all the tumors in the cohort. These data support the clinical development of a merlin IHC test for evaluation of NF2-mutated malignant mesothelioma. Merlin IHC will be used as a predictive biomarker for responsiveness to defactinib, a selective and potent FAK inhibitor under investigation in a Phase 2 registration-directed clinical trial for patients with MPM. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A31. Citation Format: David T. Weaver, Irina Shapiro, Christian Vidal, Qunli Xu, Mahesh Padval, Jonathan Pachter, Daniel Paterson, Jullianne Barlow, William Richards, Sabina Signoretti, Raphael Bueno. Merlin loss as a biomarker for defactinib (VS-6063) sensitivity: High frequency in malignant mesothelioma tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A31.
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