Selective targeting of BCL2 with the BH3-mimetic venetoclax is proving transformative for patients with various leukemias. TP53 controls apoptosis upstream from where BCL2 and its pro-survival relatives, such as MCL1, act. Therefore, targeting these pro-survival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL2 has produced clinically relevant responses in blood cancers with aberrant TP53. However, we show that TP53 mutated or deficient myeloid and lymphoid leukemias outcompete isogenic controls with intact TP53, unless sufficient concentrations of BH3-mimetics targeting BCL2 or MCL1 are applied. Strikingly, tumor cells with TP53 dysfunction escape and thrive over time if inhibition of BCL2 or MCL1 is sub-lethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study reveals the key role of TP53 in shaping long-term responses to BH3-mimetic drugs and reconciles the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia (CLL) or acute myeloid leukemia (AML). In contrast to BH3-mimetics targeting just BCL2 or MCL1 at doses which are individually sub-lethal, we find that a combined BH3-mimetic approach targeting both pro-survival proteins enhances lethality and durably suppresses leukemic burden, regardless of TP53 mutation status. Our findings highlight the importance of employing sufficiently lethal treatment strategies to maximize outcomes for patients with TP53-mutant disease. In addition, our findings caution against use of sub-lethal BH3-mimetic drug regimens, which may enhance the risk of disease progression driven by emergent TP53 mutant clones.
Rachel Thijssen, Sarah T Diepstraten, Donia M Moujalled, Edward Chew, Christoffer Flensburg, Melissa Xiaoqing Shi, Michael A Dengler, Veronique Litalien, Sarah MacRaild, Maoshan Chen, Natasha S Anstee, Boris Reljic, Sarah S Gabriel, Tirta M Djajawi, Chris D Riffkin, Brandon James Aubrey, Catherine Chang, Lin Tai, Zhen Xu, Thomas David Morley, Giovanna Pomilio, Claudia Bruedigam, Axel Kallies, David A Stroud, Ashish Bajel, Ruth M Kluck, Steven W Lane, Marie Schoumacher, Sébastien Banquet, Ian J Majewski, Andreas Strasser, Andrew W Roberts, David Ching Siang Huang, Fiona C Brown, Gemma Kelly, Andrew H Wei