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MEK inhibitor trametinib increases CXCL10 expression and this protein, secreted from tumor cells, produces T cell recruitment and enhances chemoimmunotherapy efficacy
A recent study published on Cancer Cell has shown that adding a MEK inhibitor to a standard therapy with platinum and pemetrexed can enhance the chemoimmunotherapy efficacy in in vitro and in vivo models of lung cancer: a commentary published on Cell Reports Medicine now explains the relevancy of these results.
Authors say that front-line treatment for metastatic non small cells lung cancer include treatment with immune checkpoint blockade alone or with a platinum-based chemotherapy with taxane or pemetrexed, depending on histology. Despite high response rates and improved progression-free or overall survival, durable responses indicative of effective immune engagement are observed in less than 50% of patients receiving the chemoimmunotherapy combination, with a response lacking moslty in patients with low levels of PD-L1 expression, suggesting that patients without significant tumor immune infiltration at baseline are less likely to respond. Identifying new combination strategies that may enhance the durable immunologic response will improve clinical outcomes for these patients and results of the Cancer Cell study are in line with this: the authors observed that augmentation of the CXCL10 levels may reinvigorate the T cell recruitment and immune response, so they performed a drug screen with clinically available kinase inhibitors and showed that the MEK inhibitor trametinib enhanced the T cell infiltration and also induced a prominent upregulation of PD-L1, by a dose-dependent increase of CXCL10 expression and release from tumor cells. In a murine in vivo model, trametinib with chemoimmunotherapy enhanced survival and improved tumor growth inhibition.
CXCL10 seems critical for T cell recruitment and necessary to restore immune checkpoint blockade efficacy within cisplatin/pemetrexed treated tumors: the utilization of effective combination approaches that are guided by biomarkers such as CXCL10 could produce better outcomes for non small cells lung cancer patients.