Abstract 3873: Candidate drug screening for TP53-mutated AML
Authors: Gwak Daehyeon , Kim Dong Chan , Jang Heejun , Liu Jun , Byun Ja Min , Hong Junshik , Shin Dong Yeop , Yoon Sung-Soo 
Published: April 2023

Abstract
Acute myeloid leukemia (AML) is a clonal blood malignancy characterized by arrested maturation and abnormal proliferation of hematopoietic precursor cells. This paralysis of normal bone marrow function leads to severe decreased immune function and bleeding tendency, and if not treated, it is an acute disease that dies within a few months due to rapid progression of AML. TP53 mutations occur in 5% to 10% of patients with de-novo acute myeloid leukemia (AML), with higher frequency in patients with relapsed/refractory AML. The treatment approach for many years has used combination chemotherapy, with usually an anthracycline and cytarabine as the foundation. These induction therapy's complete response is achieved in 60 to 85% of adults who are 60 years of age or younger. In patients who are older than 60 years of age, complete response rates are inferior 40 to 60%. TP53 mutated acute myeloid leukemia (AML) responds poorly to the conventional induction therapy and has a short overall survival rate with a median of 5-9 months. Poor outcomes in TP53 mutated AML following chemotherapy have been observed and treatment options remain limited. Therefore, this study attempted to explore the drug candidates for effective treatment of TP53 mutated AML. To study the cellular response to TP53-targeted therapy, we used the human AML cell line Kasumi-1, which harbors a homozygous TP53 mutation. We treated Kasumi-1 cells with cytarabine and Idarubicin combi-treatment. And we produced Drug Tolerant Persisters (DTPs) which is a minor population of cancer cells may evade cell death from chemotherapy and targeted therapy by entering a reversible slow proliferation state. Similar to a previously described DTP phenotype the DTPs that survive cytarabine and Idarubicin combi-treatment displayed cell-cycle arrest and resistance to further cytarabine and Idarubicin combi-treatment. And we selected 125 drug candidates that would be effective for TP53 mutated AML through in silico analysis and therapy strategies targeting p53. The drug candidates are composed of Compounds with the ability to reactivate mutant p53, Compounds directly target mutant p53, Synthetic lethal partners with mutant p53, and Compounds with the ability to anti-Leukemic Stem Cell and antineoplastic. We single out 46 of the 125 compounds for functional validation in DTPs. We chose these compounds because many of them are similar subtypes, suggesting they may have a common effect and mechanism. Using in vitro Cytotoxicity assay, we screened 46 candidate compounds at multiple doses and confirmed several drugs that effectively eliminate DTPs. Collectively, our study indicates that the combination of conventional drug and validated drug has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in TP53-mutant AML.
Citation Format: Daehyeon Gwak, Dong Chan Kim, Heejun Jang, Jun Liu, Ja Min Byun, Junshik Hong, Dong Yeop Shin, Sung-Soo Yoon. Candidate drug screening for TP53-mutated AML. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3873.