EGFR-TKI in EGFR-mutant NSCLC has been a major breakthrough. However, EGFR-TKIs leads to acquired resistance, often a lethal event. The emergence of immune checkpoint inhibitors that reverse cancer immunosuppression and enhance antitumor immunity but have yielded disappointing results for patients with an EGFR mutation. Mutated tumors generally have lower PD-L1 expression and lower mutation burden. Elucidating the factors that drive the lack of sensitivity to checkpoint inhibitors is a crucial issue, and novel combination approaches are urgently needed in this patient population.
To address this, we have developed the in-vitro models of acquired resistance (AR models). RNA-seq analysis of these AR models revealed lower antigen presentation, alteration PD-L1 expression and EMT gene expression in tumor cells. We further used these AR models to identify therapeutic strategies that could overcome resistance. This drug screen revealed that aurora kinase inhibitors exhibited strong synergy with EGFR-TKI to abrogate cell proliferation and induced potent apoptosis. Moreover, this novel combination altered the expression of certain immunomodulatory genes and hence have a capacity to restore the efficacy of immune response.