Prediction of venetoclax activity in precursor B-ALL by functional assessment of apoptosis signaling

Abstract

Deregulated cell death pathways contribute to leukemogenesis and treatment failure in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Intrinsic apoptosis signaling is regulated by different proapoptotic and antiapoptotic molecules: proapoptotic BCL-2 homology domain 3 (BH3) proteins activate prodeath molecules leading to cellular death, while antiapoptotic molecules including B-cell lymphoma 2 (BCL-2) prevent activation of prodeath proteins and counter-regulate apoptosis induction. Inhibition of these antiapoptotic regulators has become a promising strategy for anticancer treatment, but variable anticancer activities in different malignancies indicate the need for upfront identification of responsive patients. Here, we investigated the activity of the BCL-2 inhibitor venetoclax (VEN, ABT-199) in B-cell precursor acute lymphoblastic leukemia and found heterogeneous sensitivities in BCP-ALL cell lines and in a series of patient-derived primografts. To identify parameters of sensitivity and resistance, we evaluated genetic aberrations, gene-expression profiles, expression levels of apoptosis regulators, and functional apoptosis parameters analyzed by mitochondrial profiling using recombinant BH3-like peptides. Importantly, ex vivo VEN sensitivity was most accurately associated with functional BCL-2 dependence detected by BH3 profiling. Modeling clinical application of VEN in a preclinical trial in a set of individual ALL primografts, we identified that leukemia-free survival of VEN treated mice was precisely determined by functional BCL-2 dependence. Moreover, the predictive value of ex vivo measured functional BCL-2 dependence for preclinical in vivo VEN response was confirmed in an independent set of primograft ALL including T- and high risk-ALL. Thus, integrative analysis of the apoptosis signaling indicating mitochondrial addiction to BCL-2 accurately predicts antileukemia activity of VEN, robustly identifies VEN-responsive patients, and provides information for stratification and clinical guidance in future clinical applications of VEN in patients with ALL.

The limitations of targeting MEK signalling in Glioblastoma therapy

“…Furthermore, the inability of Trametinib to potently sensitize GB cells for cell death, might be due to its inability to break the intrinsically high resistance to apoptosis exhibited by GB cells. ERK is described to affect cell death via modulation of the Bcl-2 family 60 , which only plays a relative minor role in GB [61][62][63][64] compared to, for example, in leukaemia, where blocking Bcl-2 can be sufficient to induce apoptosis 65 . However, ERK is also involved in immune-resistance/immune-escape of cancer cells 60 , a potential interesting therapeutic avenue not addressed by this work.…”

Pediatric acute lymphoblastic leukemia

“…Deregulated cell death pathways contribute to treatment failure in ALL. 131 Preclinical studies have identified activities of venetoclax against high-risk leukemias such as ETP ALL, KMT2A-rearranged ALL, TCF3-HLF-positive ALL, and hypodiploid ALL (Table 2). 132,133 Proteasome and mTOR inhibitors have shown efficacy in relapsed ALL.…”

Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B‐cell acute lymphoblastic leukemia

“…Copy number alterations of genes and chromosomal arms were assessed by Multiplex Ligation‐dependent Probe Amplification (MLPA) with SALSA MLPA P335‐B2 ALL‐IKZF1 probemix and SALSA MLPA P181‐B1 Centromere probemix (MRX‐Holland, The Netherlands), according to manufacturer's instructions. The presence of fusion transcripts was analyzed by RT‐PCR as previously described …”

“…The presence of fusion transcripts was analyzed by RT-PCR as previously described. 30 Expression of DIPK1C, MTX2, TSPAN7 and TNFRSF1A as biomarker of SM sensitivity Expression of DIPK1C, MTX2, TSPAN7 and TNFRSF1A was assessed by qRT-PCR in BCP-ALL cell lines and xenografts.…”