This study was conducted to define the synergistic effect of the PI3K inhibitor BKM120 with the pan-Aurora kinase inhibitor danusertib and the potential mechanism of resistance to the combined inhibitor treatment in Burkitt lymphoma cell lines. The combination of danusertib and BKM120 showed a synergistic effect on Namalwa cells but not on BJAB cells. The combined treatment led to ERK hyperactivation and induced IL-6 secretion in BJAB cells but not in Namalwa cells. A blockade of ERK signaling with trametinib suppressed the combination treatment-induced ERK activation, reduced IL-6 mRNA expression, and downregulated IL-6R mRNA expression, resulting in an improvement in the antitumor effect. We stepwise treated Namalwa cells with both inhibitors using on-and-off treatment cycles and found that Namalwa cells gained chemoresistance by activating the ERK/IL-6 feedback loop, suggesting that the ERK-dependent IL-6 positive feedback loop can compensate for AKT inactivation and is closely associated with adaptive resistance and relapse.