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 <i>BCL2</i> 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 <i>BCL2</i>-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 <i>BCL2</i>-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 <i>BCL2</i>-rearranged lymphomas rapidly downregulated the p53 target CDKN1A (p21) in response to Bcl2 inhibition <i>in vivo</i>. 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.