Therapeutic efficacy of BET bromodomain protein inhhibitor and PD-1 blockade in genetically engineered mouse model of non-small cell lung cancer

KRAS mutation is present in about 30% of human lung adenocarcinomas. While recent advances in targeted therapy have shown great promise, KRAS remains undruggable and concurrent alterations in tumor suppressors render KRAS mutant tumors even more resistant to existing therapies. Contributing to the refractoriness of KRAS mutant tumors harboring these co-mutations are immunosuppressive mechanisms such as increased presence of suppressive Tregs in tumors and elevated expression of the inhibitory receptor PD-1 on tumor-infiltrating T cells. BET bromodomain inhibitors demonstrate clinical benefit in hematologic malignancies, and prior reports demonstrate their Treg-disruptive effects in a NSCLC model. Targeting PD-1 inhibitory signals through anti-PD-1 antibody blockade has also shown substantial therapeutic impact in lung cancer although these outcomes are still limited to a minor pool of patients. We therefore hypothesized that the BET bromodomain inhibitor JQ1 would synergize with PD-1 blockade to promote robust anti-tumor response in lung cancer. In the present study, using Kras+/LSL-G12D; Trp53L/L (KP) mouse models of non-small cell lung cancer, we identified cooperative effects between JQ1 and anti-PD-1 antibody that included reduced numbers of tumor-infiltrating Tregs and enhanced activation of tumor-infiltrating T cells, which exhibited a Th1 cytokine profile that favored their demonstrated improved effector function. Furthermore, lung-tumor-bearing mice under this combinatorial treatment regimen showed robust and long-lasting anti-tumor responses compared to either agent alone, culminating in substantial improvement in the survival of treated mice. Thus, combining BET bromodomain inhibition with immune checkpoint blockade offers a promising therapeutic approach for solid malignancies such as lung adenocarcinoma. Overall design: Gene expression analyses of tumor nodules in lung tumor-bearing mice treated with Vehicle (control), JQ1 (Bromodomain inhibitor) and/or anti-PD-1 antibody

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Adeegbe DO, Liu S, Hattersley MM, Bowden M, Zhou CW, Li S, Vlahos R, Grondine M, Dolgalev I, Ivanova EV, Quinn MM, Gao P, Hammerman PS, Bradner JE, Diehl JA, Rustgi AK, Bass AJ, Tsirigos A, Freeman GJ, Chen H, Wong KK