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

Abstract

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.

Keywords:

• Burkitt lymphoma
• BKM120
• danusertib
• chemoresistance
• Aurora kinase
• PI3K

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2019.1594211.

Additional information

Funding

Hong J. received the Research Resettlement Fund for the new faculty of Seoul National University. Yoon SS received the National Research Foundation of Korea (NRF) Grant funded by the Korean Government (MSIP) (No. NRF-2016R1A5A1011974).