Trametinib sensitizes KRAS-mutant lung adenocarcinoma tumors to PD- 1/PD-L1 axis blockade via Id1 downregulation

Abstract Background The identification of novel therapeutic strategies to overcome the intrinsic or acquired resistance to trametinib in mutant KRAS lung adenocarcinoma (LUAD) is a major challenge. This study analyzes the effects of trametinib in Id1, a key factor involved in the oncogenic KRAS pathway, and investigates the Id1 role in acquire resistance and trametinib synergy with immunotherapy in KRAS-driven LUAD.Methods We evaluated the effects of trametinib in KRAS-mutant LUAD tumors by western blot, RNA-seq and syngeneic mouse models. Cell viability was assessed by cell proliferation and colony formation assays. PD-L1 expression and apoptosis was measured by flow cytometry. The anti-tumor efficacy of the trametinib and PD-1 blockade combined treatment was investigated in two KRAS-driven LUAD mouse models, and the effects in the tumor immune infiltrate was analyzed by immunohistochemistry.Results We found that trametinib activates the proteasome to downregulate Id1 expression in KRAS-mutant LUAD cells and tumors. Moreover, Id1 inhibition overcome the acquire resistance to trametinib in KRAS-mutant LUAD cells. Using two preclinical syngeneic KRAS-driven LUAD mouse models we found that trametinib synergizes with PD-1 blockade to hamper lung cancer progression and increase survival. This anti-tumor activity was associated with an increase of the intratumoral CD8+/Treg ratio and PD-L1 expression on LUAD cells surface.Conclusions Our data suggests that Id1 may be involved in the resistance to trametinib and in the synergy with immunotherapy in KRAS-driven LUAD tumors. These findings suggest a potential therapeutic approach for refractory KRAS-mutant lung cancers.