TP53 upregulation via aurora kinase inhibition overcomes primary failure to venetoclax in BCL2-rearranged lymphomas.

Bcl2 inhibition has excellent antitumor activity against hematologic malignancies. However, the clinical results in lymphomas harboring BCL2 gene rearrangements have been disappointing, and the mechanism of this intrinsic resistance remains unknown. Herein, we report that Bcl2 inhibition rapidly repressed p53 with poor response in BCL2-rearranged lymphoma cells. However, concurrent inhibition of aurora kinase (Aurk) overcame this primary resistance to Bcl2 inhibition by restoring the p53/p21 proapoptotic axis via a post-transcriptional increase in p53. Two independent BCL2-rearranged lymphoma murine models showed complete tumor regression in all animals treated with combined Bcl2/Aurk inhibition, whereas mice treated with single-agents demonstrated rapid progression. Transcriptome analysis confirmed that BCL2-rearranged lymphomas rapidly downregulated the p53 target CDKN1A (p21) in response to Bcl2 inhibition in vivo. However, concurrent inhibition of Aurk restored the TP53/CDKN1A pathway, sensitizing the tumors to Bcl2 inhibitor-mediated apoptosis. These data lay the groundwork for evaluation of this combination in the clinical setting.