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Understanding Why The Anti-Cancer Drug, Pembrolizumab, Fails In Certain Patients

Melanoma is one of the fastest growing cancers in the U.S. and is attributed to 75% of all skin cancer deaths. Modern immunotherapy cancer drug treatments, which activate the immune system to fight against tumors, have been developed, including the recently FDA-approved drug Pembrolizumab (Pembro), or KEYTRUDA®. While Pembro has successfully treated numerous melanoma patients, including former President Jimmy Carter, it has also been documented to paradoxically promote rapid tumor growth in a small subset of patients. Next-generation sequencing has identified a damaging JAK-STAT signaling pathway mutation in these tumors, potentially linking this pathway to these failed treatments. Our goal was to better understand the molecular basis of how Pembro immunotherapy counterintuitively promotes cancer, given this mutation.  It was hypothesized that an increased immune response, caused by Pembro treatment, leads to overstimulation of the mutated pathway in cells, leading to undesirable proliferation. Methods/Results: In a series of cell culture experiments, we treated patient-derived cell lines, with and without the mutation, with Pembro and measured common cellular markers associated with cancer aggressiveness/proliferation. Melanoma cells with the mutation that were treated with Pembro had higher proliferative marker levels than untreated cells with the mutation or cells without the mutation. Conclusion: Our preliminary findings suggest that this specific mutation, in conjunction with Pembro administration, leads to greater melanoma proliferation. This enhanced understanding of the dynamic interactions between Pembrolizumab, the immune system, and this mutated pathway may lead to a better decision of when and when not to administer Pembrolizumab to patients.