Abstract
The successes of targeted therapeutics against EGFR and ALK in non-small cell lung cancer (NSCLC) have demonstrated the substantial survival gains made possible by precision therapy. However, the majority of patients do not have tumors with genetic alterations responsive to these therapies, and therefore identification of new targets is needed. Our laboratory previously identified MER receptor tyrosine kinase as one such potential target. We now report our findings targeting MER with a clinically translatable agent--Mer590, a monoclonal antibody specific for MER. Mer590 rapidly and robustly reduced surface and total MER levels in multiple cell lines. Treatment reduced surface MER levels by 87%, and this effect was maximal within four hours. Total MER levels were also dramatically reduced, and this persisted for at least seven days. Mechanistically, MER down-regulation was mediated by receptor internalization and degradation, leading to inhibition of downstream signaling through STAT6, AKT, and ERK1/2. Functionally, this resulted in increased apoptosis, increased chemosensitivity to carboplatin, and decreased colony formation. In addition to carboplatin, Mer590 interacted cooperatively with shRNA-mediated MER inhibition to augment apoptosis. These data demonstrate that MER inhibition can be achieved with a monoclonal antibody in NSCLC. Optimization toward a clinically available anti-MER antibody is warranted.
Highlights
Optimization of conventional chemotherapy regimens has led to modest gains in survival in non-small cell lung cancer (NSCLC) over the past few decades, and studies suggest that new treatment strategies must be pursued in order to achieve more impressive clinical gains [1,2,3]
As total MER decrease was consistent in all four NSCLC cell lines assayed, we selected two representative cell lines for further study: Colo699 because it does not express AXL and is MER-dependent, and H2009 as a representative cell line expressing both MER and AXL
Like total MER expression, surface MER expression as measured by flow cytometry was decreased after Mer590 treatment, with a reduction of 87% after 48 hours of treatment in the Colo699 cell line (Figure 1B)
Summary
Optimization of conventional chemotherapy regimens has led to modest gains in survival in NSCLC over the past few decades, and studies suggest that new treatment strategies must be pursued in order to achieve more impressive clinical gains [1,2,3] Toward this end, therapies that target specific molecular aberrations in NSCLC cells have begun to emerge. Small molecule tyrosine kinase inhibitors directed against mutated EGFR or ALK fusion proteins have transformed treatment outcomes for the ~10% and ~4%, respectively, of Western NSCLC patients whose tumors are driven by one of these activated oncogenes This has improved survival over conventional chemotherapeutics while offering a more tolerable side effect profile [4,5,6,7,8]. Identification of novel targets is a priority in order to increase the number of patients who will benefit from biologically-oriented therapeutics
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