Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias

Abstract

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.

SOHO State of the Art Updates and Next Questions: Harnessing Apoptosis in AML

“…18 , 41 Elegant preclinical models have demonstrated that this outgrowth of TP53-mutant clones occurs when venetoclax is used alone as well as in combination with cytarabine or decitabine. 41 However, when venetoclax is combined with an MCL-1 inhibitor (but not when an MCL-1 inhibitor is used alone or with cytarabine or decitabine), both TP53-mutant and wild-type clones can be eradicated, providing a novel potential approach for treating patients with TP53-mutated AML. 41 The etiology of this synergy between combined BCL-2 and MCL-1 inhibition in TP53-mutated AML remains unclear, although it may be attributable to decreased priming for intrinsic apoptosis in TP53-mutated cells, thereby requiring inhibition of multiple antiapoptotic proteins to prevent the eventual outgrowth of a resistant clone during sublethal inhibition of BCL-2 or MCL-1.…”

“…41 However, when venetoclax is combined with an MCL-1 inhibitor (but not when an MCL-1 inhibitor is used alone or with cytarabine or decitabine), both TP53-mutant and wild-type clones can be eradicated, providing a novel potential approach for treating patients with TP53-mutated AML. 41 The etiology of this synergy between combined BCL-2 and MCL-1 inhibition in TP53-mutated AML remains unclear, although it may be attributable to decreased priming for intrinsic apoptosis in TP53-mutated cells, thereby requiring inhibition of multiple antiapoptotic proteins to prevent the eventual outgrowth of a resistant clone during sublethal inhibition of BCL-2 or MCL-1. 41 Trials assessing the combination of BCL-2 and MCL-1 inhibitors are currently ongoing for patients with AML, including an international phase Ib study assessing venetoclax + the MCL-1 inhibitor S64315 (NCT03672695).…”

“…41 The etiology of this synergy between combined BCL-2 and MCL-1 inhibition in TP53-mutated AML remains unclear, although it may be attributable to decreased priming for intrinsic apoptosis in TP53-mutated cells, thereby requiring inhibition of multiple antiapoptotic proteins to prevent the eventual outgrowth of a resistant clone during sublethal inhibition of BCL-2 or MCL-1. 41 Trials assessing the combination of BCL-2 and MCL-1 inhibitors are currently ongoing for patients with AML, including an international phase Ib study assessing venetoclax + the MCL-1 inhibitor S64315 (NCT03672695). Another potential means of improving outcomes for patients with TP53-mutated AML is by "restoring" native p53 function, such as with the compound APR-246 (eprenetapopt).…”

A novel CRISPR activation mouse enables modelling of aggressive lymphoma and interrogation of venetoclax resistance.

“…19 Identifying resistance factors to venetoclax therapy is therefore an area of great clinical relevance. Whilst CRISPR gene knock-out screens have identi ed TP53 loss and other factors that are mediators of venetoclax resistance, 20,21 no studies have utlised CRISPRa to investigate genes that can confer venetoclax resistance when upregulated from their endogenous promoters. Cell lines derived from the CRISPRa mouse model of DHL that are highly sensitive to venetoclax provide an ideal platform to perform genome-wide CRISPRa screens for identifying resistance factors.…”

Targeting MCL-1 and BCL-2: a 1-2 punch

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In this issue of Blood, Thijssen et al report that leukemia or lymphoma cells with TP53 loss have a selective advantage over time when treated with sublethal doses of a BCL-2 or MCL-1 inhibitor, because of reduced activation of BAX and BAK, but this defect can be overcome with dual treatment with both inhibitors. 1

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