Abstract 6918: Ba/F3-BCR-ABL engineering cell line panel, a useful platform for novel drug discovery

Abstract

Abstract In the past few years, with the great success of Imatinib, the first kinase inhibitor, Imatinib rapidly became the first-line treatment for CML (Chronic myelogenous leukemia) carrying the BCR-ABL mutation. It opened a new chapter in targeted cancer treatment. Despite the increase in overall survival allowed by imatinib, the onset of drug resistance led scientists to investigate imatinib's fine structural mechanism of action to develop new and more effective compounds against mutated forms of Bcr-Abl. 7 BCR-ABL inhibitors have been approved, they are Imatinib, Dasatinib, Nilotinib, Bosutinib, Ponatinib, Olverembatinib, and Asciminib. However, acquired resistance has been a major challenge in the treatment of CML, and some patients still experience disease progression or even death due to drug resistance. BCR-ABL kinase domain mutations are one of the important mechanisms of acquired resistance, with the T315I mutation being the most common type of drug resistance mutation, accounting for approximately 25% of drug-resistant CML cases. Patients with T315I mutations in CML are resistant to all current first- and second-generation BCR-ABL inhibitors. Asciminib is designed as an allosteric inhibitor combined with an ATP-competitive TKI agent, which may hinder the development of mutation-driven acquired resistance or restore efficacy against highly resistant BCR-ABL mutants. Our group has generated 38 Ba/F3-BCR-ABL engineering cell lines as useful models for novel drug discovery in vitro and in vivo, including wild-type BCR-ABL and inhibitors leading drug resistance mutations, such as T315I, E255, Y253, F317, F359. V299, G250, A337T, V468F, and double mutations. Each cell was validated by cell sequencing and cell efficacy verification using approved BCR-ABL inhibitors. The Ba/F3-BCR-ABL engineering cell line panel can be useful for developing and evaluating next-generation BCR-ABL inhibitors and exploring newly acquired resistance mutations in BCR-ABL. Citation Format: Guoqian Wang, Yao Peng, Yu Wang, Yao Tang, Jingxiao Xu, Jinying Ning, Feng Hao. Ba/F3-BCR-ABL engineering cell line panel, a useful platform for novel drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6918.