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

ABSTRACT: Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones.

SUBMITTER: Thijssen R

PROVIDER: S-EPMC8138548 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionLarge cell neuroendocrine carcinoma (LCNEC) is a rare and highly aggressive high-grade neuroendocrine neoplasm, which can arise from anywhere in the body. Due to its rarity there is a lacuna in our understanding of LCNEC's molecular biology. In 2016, Rekhtman and colleagues presented one of the largest molecular sequencing series of pulmonary LCNEC. They differentiated genomic profiles of LCNEC into two major subsets: small cell lung cancer (SCLC)-like, characterized by TP53 + RB1 co-mutation/loss, and non-small cell lung cancer (NSCLC)-like, characterized by the lack of co-altered TP53 + RB1. This finding is of significance because at present LCNEC patients are often treated like SCLC. However, the universal genomic SCLC biomarker of TP53 and RB1 co-mutation was only found in 40% of their cohort. Since then various other scientists have looked into molecular profiling of LCNEC with markedly discordant results. The objective of this study was to conduct a systematic review of publicly available next generation sequencing (NGS) data to evaluate the prevalence of TP53 + RB1 co-mutation in LCNEC.MethodWe conducted a literature search using PubMed. Seven studies including 302 patients with pulmonary LCNEC and four studies including 20 patients with extra-pulmonary LCNEC underwent final analysis.ResultsThe prevalence of TP53 + RB1 co-mutation was 36% (109/302) among pulmonary LCNEC patients and 35% (7/20) among the extra-thoracic LCNEC cohort. This finding is in stark contrast to >90% TP53 + RB1 co-mutation in SCLC.ConclusionIt is now well established that LCNEC is molecularly distinct from SCLC. LCNEC seems to have two molecularly defined sub-cohort based on TP53 + RB1 co-mutation status. Future studies should look into prognostic and predictive implication of TP53 + RB1 co-mutation status in LCNEC. Prospective studies should be designed to characterize molecular subtypes and direct treatment accordingly. We are currently conducting a prospective pilot clinical trial wherein LCNEC patients are treated based on TP53 + RB1 co-mutation status. The study is currently enrolling. "Next Generation Sequencing-Based Stratification of Front Line Treatment of Neuroendocrine Carcinoma (PRECISION-NEC).Systematic reviewClinicalTrials.gov, identifier NCT04452292.

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

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