ERK-dependent IL-6 positive feedback loop mediates resistance against a combined treatment using danusertib and BKM120 in Burkitt lymphoma cell lines

• Published in: Leukemia & lymphoma Vol. 60; no. 10; pp. 2532 - 2540
• Main Authors: Liu, Jun, Hong, Junshik, Ahn, Kwang-Sung, Go, Junhyeok, Han, Heejoo, Park, Jihyun, Kim, Dongchan, Park, Hyejoo, Koh, Youngil, Shin, Dong-Yeop, Yoon, Sung-Soo
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 24.08.2019
• Subjects: Aurora kinase; BKM120; Burkitt lymphoma; chemoresistance; danusertib; PI3K; chemoresistance; Aurora kinase; danusertib; PI3K; Burkitt lymphoma; BKM120
• ISSN: 1042-8194; 1029-2403
• DOI: 10.1080/10428194.2019.1594211

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.