Project Details
Projekt
Identification of resistance mechanisms for therapy of venetoclax-refractory high-risk CLLs
Applicant
Dr. Lukas Frenzel
Subject Area
Hematology, Oncology
Term
from 2016 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 226262100
The coming decade might become the most challenging for CLL treatment - with an enormous potential to cure this disease, but also with relevant obstacles. Novel, non-genotoxic compounds, which specifically target Achilles heels of CLL cells, such as mitochondria (BH3 mimetics; ABT-199), or the B-cell receptor (tyrosine kinase inhibitors, TKIs; ibrutinib, idelalisib), will complement or even replace classical chemo-immune-based regimens. Indeed, results from first clinical trials in heavily pretreated patients exceeded all expectations, since treatment with ABT-199 or TKIs dramatically improved the response rates. Our data revealed CLL cells to be resistant to extrinsic apoptosis mediated by death receptors, but sensitive towards the intrinsic apoptosis pathway, which is targeted by ABT-199, as it was shown by us and others. Moreover we could show for the first time that ABT-199 acts synergistically with ibrutinib and idelalisib. However, first data from longer follow-up clinical trials indicate that ABT-199 results in so far unknown resistance mechanisms accompanied by a very aggressive course of disease with a high mortality. Our preliminary results uncover, that acquired resistance against BH3 mimetics in vitro might be due to loss of BAK1 and BAX function. Fresquet et al. found in pre-clinical settings that acquired resistance towards ABT-199 relies on mutations in BCL-2 and BAX. Loss of function of BAX and BAK1 might result in a complete block of intrinsic apoptosis, since both are direct executioners of mitochondrial apoptosis. Clinical trials with the novel drugs inbrutinib and ABT-199 indicate that patients with high-risk settings like loss p53 have the worst outcome, supporting the hypothesis that also non-genotoxic compounds rely on functional p53. Indeed, p53 induces the extrinsic and intrinsic apoptotic pathways to ensure an efficient death response. Our findings clearly show that CLL cells are resistant towards extrinsic apoptosis, but sensitive to intrinsic apoptosis. Once CLL cells also acquire a block in intrinsic apoptosis during the course of e.g. ABT-199 treatment under p53-deficient settings, we hypothesize that this might have severe impact on further treatment options. Based on these considerations, we will pursue a tailored experimental path to tackle three specific aims:1) elucidate and validate the mechanisms of p53-dependent resistance against ABT-199, 2) characterize the functional relevance of the novel BAK1R127L mutant and 3) identify treatment options to overcome Bak1/Bax deficiency in CLL. Our aims will directly test the hypotheses that: 1) resistance mechanisms towards ABT-199 are dependent on p53 as a critical upstream regulator of mitochondrial apoptosis, 2) resistance towards ABT-199 does not occur solely on the level of DNA mutations, and 3) Bak1/Bax-deficiency can be overcome pharmacologically. To achieve our goals we will employ novel mouse models, genomics/bioinformatics, epigenomics and molecular biology.
DFG Programme
Clinical Research Units
