Blood cancer journal · 2025
Superior preclinical efficacy of co-treatment with BRG1/BRM and FLT3 inhibitor against AML cells with FLT3 mutations.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Fiskus Warren, Mill Christopher P, Piel Jessica, Collins Mike, Hentemann Murphy, Cuglievan Branko, Birdwell Christine E, Das Kaberi, Hou Hanxi, Davis John A, Jain Antrix, Malovannaya Anna, Kadia Tapan M, Daver Naval, Sasaki Koji, Takahashi Koichi, Hammond Danielle, Reville Patrick K, Flores Lauren B, Loghavi Sanam, Su Xiaoping, DiNardo Courtney D, Bhalla Kapil N
Аннотация
Although treatment with standard frontline therapies, including a FLT3 inhibitor (FLT3i) reduces AML burden and achieves clinical remissions, most patients with AML with FLT3 mutation relapse due to therapy-resistant stem/progenitor cells. The core ATPases, BRG1 (SMARCA4) and BRM (SMARCA2) of the canonical (c) BAF (BRG1/BRM-associated factor) complex is a dependency in AML cells, including those harboring FLT3 mutations. We have previously reported that treatment with FHD-286, a BRG1/BRM ATPases inhibitor, induces differentiation and loss of viability of AML stem/progenitor cells. Findings of present studies demonstrate that treatment with FHD-286 induces lethality in AML cells, regardless of sensitivity or resistance to FLT3i. This efficacy is associated with the induction of gene-expression perturbations responsible for growth inhibition, differentiation, as well as a reduced AML-initiating potential of the AML cells. Additionally, co-treatment with FHD-286 and FLT3i exerts superior pre-clinical efficacy against AML cells and patient-derived (PD) xenograft (PDX) models of AML with FLT3 mutations.