Article
Oncology
Yi Liu, Jing Wei, Jiaxin Liu, Weina Ma, Yanting Duan, Daihong Liu
Summary: The study investigated the upregulation of AXL antigen expression in FLT3-ITD+ AML blast cells, as well as the cytotoxic effects of novel AXL-targeted agents on FLT3-mutant AML cell lines and blast cells. Combinations of AXL-targeted agents with AC220 showed synergistic cytotoxic effects and induced apoptosis in FLT3 inhibitor-resistant blast cells. The antileukemic effect of AXL-targeted agents may rely on their ability to block AXL, FLT3 and their downstream signaling pathways.
Review
Biochemistry & Molecular Biology
Moo-Kon Song, Byeong-Bae Park, Ji-Eun Uhm
Summary: FLT3 mutations are the most common genetic alterations in AML and have a negative impact on clinical prognosis. The development of FLT3 inhibitors has shown promise in improving outcomes for AML patients with FLT3 mutations. Midostaurin and gilteritinib have recently been approved as frontline treatments for AML by the FDA. Clinical trials are ongoing to explore the use of FLT3 inhibitors in different treatment settings. The accumulation of data on FLT3 inhibitors will be important evidence for guiding the use of these inhibitors in AML patients with FLT3 mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Review
Medicine, General & Internal
Matteo Molica, Salvatore Perrone, Marco Rossi
Summary: The introduction of tyrosine kinase inhibitors (TKI) into clinics has improved the traditionally poor outcome of acute myeloid leukemia (AML) patients carrying the FMS-related tyrosine kinase 3 (FLT3) mutations. This review summarizes the clinical data that led to the use of gilteritinib, a second-generation TKI, in clinical practice. Gilteritinib has shown deeper single-agent activity than first-generation drugs against both FLT3-ITD and TKD mutations in human studies, with an acceptable safety profile and a high overall response rate. Real-world experiences and ongoing investigations of gilteritinib-based combinations are also discussed.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Biochemistry & Molecular Biology
Fansheng Ran, Yun Liu, Jian Zhu, Xuexian Deng, Hongmei Wu, Weizhi Tao, Xudong Xie, Yirong Hu, Yanan Zhang, Yong Ling
Summary: A novel class of aminopyrimidine-based dual-target inhibitors, designed for the treatment acute myeloid leukemia, effectively inhibited the activities of BTK, FLT3, and FLT3(D835Y) mutant. These compounds showed potent antiproliferative activities against leukemia cells and induced autophagy and apoptosis. In vivo studies demonstrated that compound 14m significantly suppressed the growth of MV-4-11 cells without apparent toxicity. These dual-target inhibitors hold promise for further optimization and mechanism studies.
BIOORGANIC CHEMISTRY
(2023)
Review
Oncology
Claire Andrews, Vinod Pullarkat, Christian Recher
Summary: CPX-351, a dual-drug liposomal encapsulation of daunorubicin and cytarabine, has been approved for treating newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. In clinical trials, CPX-351 significantly improved overall survival in high-risk or secondary AML patients aged 60-75 years. FLT3 gene mutations are found in approximately 30% of newly diagnosed AML patients and may have a negative impact. CPX-351 combined with FLT3 inhibitors shows promise as a treatment option for FLT3 mutation-positive AML patients.
FRONTIERS IN ONCOLOGY
(2023)
Review
Oncology
Shuai-Shuai Ge, Song-Bai Liu, Sheng-Li Xue
Summary: FLT3 mutations are common in AML and targeting FLT3 has significantly improved survival rates. However, resistance to FLT3 inhibitors is a pressing issue, and the development of novel treatments and multitarget strategies is needed.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Hui Ma, Jiayan Cui, Zehui Liu, Wenqing Fang, Sisi Lu, Shuying Cao, Yuanyuan Zhang, Ji-An Chen, Lixue Lu, Qiong Xie, Yonghui Wang, Ying Huang, Kongfei Li, Hongyan Tong, Jin Huang, Weiqiang Lu
Summary: This study demonstrates that induction of degradation of FLT3-ITD protein by DHODH blockade may offer a promising therapeutic strategy for AML patients harboring FLT3-ITD mutation.
Article
Oncology
Mahran Shoukier, Tapan Kadia, Marina Konopleva, Ahmad S. Alotaibi, Mansour Alfayez, Sanam Loghavi, Keyur P. Patel, Rashmi Kanagal-Shamanna, Jorge Cortes, Bachar Samra, Elias Jabbour, Guillermo Garcia-Manero, Koichi Takahashi, Sherry Pierce, Nicholas J. Short, Musa Yilmaz, Koji Sasaki, Lucia Masarova, Naveen Pemmaraju, Gautam Borthakur, Hagop M. Kantarjian, Farhad Ravandi, Courtney D. DiNardo, Naval Daver
Summary: The combination of FLT3 inhibitor-based therapy with cytotoxic chemotherapy or low-intensity therapy appears to be effective in patients with FLT3-ITD/IDH co-mutated disease in both the frontline and recurrent and/or refractory settings. Fewer dual-mutated patients received cytotoxic chemotherapy or low-intensity therapy with an IDH1/2 inhibitor in the frontline setting; however, excellent responses also were observed with this approach.
Article
Cell Biology
Mohammad Houshmand, Nicoletta Vitale, Francesca Orso, Alessandro Cignetti, Ivan Molineris, Valentina Gaidano, Stefano Sainas, Marta Giorgis, Donatella Boschi, Carmen Fava, Alice Passoni, Marta Gai, Massimo Geuna, Federica Sora, Alessandra Iurlo, Elisabetta Abruzzese, Massimo Breccia, Olga Mulas, Giovanni Caocci, Fausto Castagnetti, Daniela Taverna, Salvatore Oliviero, Fabrizio Pane, Marco Lucio Lolli, Paola Circosta, Giuseppe Saglio
Summary: The study shows that the newly developed DHODH inhibitor, Meds433, is highly effective in targeting CML cells by activating the apoptotic pathway and inducing metabolic stress. This finding suggests that DHODH inhibition is a promising approach for targeting CML stem/progenitor cells.
CELL DEATH & DISEASE
(2022)
Article
Oncology
Javier Bregante, Anna Schoenbichler, Daniel Poeloeske, Lina Degenfeld-Schonburg, Garazi Monzo Contreras, Emir Hadzijusufovic, Elvin D. de Araujo, Peter Valent, Richard Moriggl, Anna Orlova
Summary: FLT3-ITD mutations are common and detrimental in AML, with AML cells quickly developing resistance to FLT3 kinase inhibitors. Through a drug screen, new potential therapeutics like ispinesib, WS6, ponatinib, and cabozantinib have been identified for FLT3-ITD+ AML. Combination therapy with cabozantinib and ispinesib shows strong efficacy against FLT3-ITD+ AML, suggesting promising novel treatment options for this clinical challenge.
Article
Cell Biology
Sivasundaram Karnan, Ichiro Hanamura, Akinobu Ota, Souichi Takasugi, Ayano Nakamura, Miyuki Takahashi, Kaori Uchino, Satsuki Murakami, Md Wahiduzzaman, Lam Quang Vu, Md Lutfur Rahman, Muhammad Nazmul Hasan, Toshinori Hyodo, Hiroyuki Konishi, Shinobu Tsuzuki, Kazuhiro Yoshikawa, Susumu Suzuki, Ryuzo Ueda, Masayuki Ejiri, Yoshitaka Hosokawa, Akiyoshi Takami
Summary: STAT5 activation in genetically modified FLT3-ITD knock-in human myeloid leukemia K562 cells upregulates CD52 expression, while the anti-CD52 antibody alemtuzumab induces antibody-dependent cell-mediated cytotoxicity (ADCC) and shows antitumor effects in FLT3(ITD/WT) cells.
CELL DEATH DISCOVERY
(2021)
Article
Biochemistry & Molecular Biology
Indira Singaram, Ashutosh Sharma, Shashank Pant, Muyun Lihan, Mi-Jeong Park, Melissa Pergande, Pawanthi Buwaneka, Yusi Hu, Nadim Mahmud, You-Me Kim, Stephanie Cologna, Vladimir Gevorgyan, Irum Khan, Emad Tajkhorshid, Wonhwa Cho
Summary: Membrane lipids control the cellular activity of kinases containing the SH2 domain. In this study, new nonlipidic small molecule inhibitors of the lipid-SH2 domain interaction were developed to block the cellular activity of their host proteins. The research shows that targeting lipid-protein interaction is a powerful approach to developing new small molecule drugs.
NATURE CHEMICAL BIOLOGY
(2023)
Article
Oncology
Corinna Spohr, Teresa Poggio, Geoffroy Andrieux, Katharina Schoenberger, Nina Cabezas-Wallscheid, Melanie Boerries, Sebastian Halbach, Anna L. Illert, Tilman Brummer
Summary: The presence of internal tandem duplications (ITD) in FMS-like tyrosine kinase 3 (FLT3) combined with DNMT3A mutations in acute myeloid leukemia (AML) leads to poor prognosis. Studies have shown that GAB2 is essential for the development of Flt3-ITD driven AML, with Gab2 deficient mice displaying prolonged survival and reduced pathology. Gab2 increases signaling of receptor tyrosine kinases, promoting AML aggressiveness and drug resistance, making it a promising biomarker and therapeutic target in human AML.
Article
Chemistry, Medicinal
Sheng Cao, Lan Ma, Yulin Liu, Mingming Wei, Yuhong Yao, Chen Li, Ruonan Wang, Ning Liu, Zhiqiang Dong, Xuechun Li, Ming Li, Xiaoji Wang, Cheng Yang, Guang Yang
Summary: In this study, dovitinib was chemically modified into CRBN-recruiting PROTACs, resulting in two active compounds with enhanced antiproliferative effects against FLT3-ITD+ AML cells and the ability to induce degradation of FLT3-ITD and KIT proteins while blocking their downstream signaling pathways. This study presents a promising strategy for developing novel therapies for FLT3-ITD+ AML.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Emmanuella Oyogoa, Lukas Streich, Philipp W. Raess, Theodore Braun
Summary: This is a case report on a 27-year-old female with chronic myeloid leukemia (CML) who developed kinase-independent resistance and disease progression. The patient initially had chronic phase (CP) CML and acquired mutations in ASXL1 and RUNX1. Due to uncontrolled disease, she progressed to a chronic myelomonocytic leukemia-like (CMML) accelerated phase (AP) disease and obtained an IDH1 mutation. The disease progression was associated with the development of an inflammatory serositis, a phenomenon not typically observed in AP-CML.
FRONTIERS IN ONCOLOGY
(2023)