Frank van Leeuwen
9B. Identifying synthetic lethal combination therapies for TP53 deleted ALL using isogenic cell line models
TP53 is the most frequently mutated gene in cancer, but with a mutation frequency of only 3% at diagnosis, its role in Acute Lymphoblastic Leukemia has been largely underexposed. However, the incidence in relapsed disease rises to 15% and particularly here, aberrations of the TP53 gene predict a dismal outcome. Hence, there is an urgent clinical need for novel strategies to eradicate TP53-mutated leukemia.
The aim of this proposal is to identify vulnerabilities of TP53-mutated BCP-ALL.
For this purpose, we introduced loss-of-function mutations in the TP53 gene using CRISPR/CAS9 to generate isogenic wildtype and knockout BCP-ALL cell lines. We will use these models in complementary reverse genetic- and drug screens.
We confirmed that TP53-deficient cells fail to respond to MDM2 antagonists. Moreover, TP53 mutant cells are resistant to chemotherapies known to induce P53-dependent apoptosis. Importantly, a small-scale drug screen, in which we tested the response to the drugs used in contemporary treatment protocols, showed that indeed TP53-mutated cells are resistant to most of these compounds, highlighting both the relevance and the urgency of developing novel treatment strategies.
We will use these models in reverse genetic (CRISPR) screens and expose these cells to drug libraries alone and in combination with the drugs that are the mainstay of contemporary treatment protocols. The focus will be on cell metabolism, as TP53 is known to play a pivotal role in metabolic regulation, presenting potential vulnerabilities in TP53 deleted ALL.
We expect integrating the data obtained in these screens will allow us to identify genes/pathways that are essential to TP53-mutated cells to survive treatment and find (metabolic) vulnerabilities that can be exploited as therapeutic target. These results will preclinically validated using a panel of patient derived xenograft models for TP53 deficient ALL that we established over the past few years.
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