作者
Priyanka Somanath,Daniel Lu,Brian K. Law,Tenley C. Archer,Tripta Rughwani,Lekha Kumar,Taisei Kinoshita,Mini Balakrishnan,Thomas W. Butler
摘要
7541 Background: Menin is a scaffold protein that drives oncogenic function through transcriptional modulation directed by its various cofactors. A previous report demonstrated that menin regulates a distinct set of gene targets independent of its function with the MLL proteins in hematopoiesis and is essential for B-cell maturation (Li et al. Blood.2013;122(12):2039-46.). Chronic Lymphocytic Leukemia (CLL) is a disease of malignant B lymphocytes, for which standard-of-care agents are generally well tolerated; however, CLL patients with certain genetic backgrounds demonstrate inferior outcomes to these regimens. A major driving feature of CLL is overexpression of the anti-apoptotic marker, BCL2. We previously reported the ability of BMF-219, a selective, irreversible menin inhibitor, to downregulate the expression of BCL2 in acute leukemia cells. Additionally, we have reported the synergy of BCL2-targeted agent, venetoclax, with BMF-219 in potent cell killing of diffuse large B-cell lymphoma (DLBCL) preclinical models, prompting our exploration of BMF-219 activity in CLL. Here, we provide the first preclinical evidence for menin as a therapeutic target in CLL, by demonstrating high potency of BMF-219 against a diverse collection of CLL patient specimens. Methods: A comprehensive panel of CLL samples isolated from patients with Rai Stage 1 to 3 disease, including relapsed or refractory disease, were cultured ex vivo in the presence of BMF-219 or clinical reversible menin inhibitors to assess the antileukemic activity of the compounds. Samples were analyzed for differential gene expression of select targets in response to treatment. Results: BMF-219 demonstrated high potency, achieving > 98% cell lethality at 1 µM exposure in all patient samples tested, with IC 50 values in the range of 0.1 to 0.38 µM. Specimens isolated from patients with clinical profiles of high-risk genetic backgrounds associated with inferior outcomes to standard therapy, such as mutations in TP53 and NOTCH1, and chromosomal aberrations such as del(13q), trisomy 12 and complex karyotype, exhibited high sensitivity to BMF-219 treatment. BMF-219 was also highly effective against patient samples with clinical profiles of resistance to bendamustine, ibrutinib and venetoclax therapy. In comparison, clinical reversible menin inhibitors demonstrated no significant activity across all patient samples tested, with incalculable IC 50 values and < 15% reduction in cell viability at 1 µM exposure. Expression of select target genes in treated CLL cell lines was explored and will be reported. Conclusions: Collectively, our data demonstrate the potent preclinical activity of BMF-219 against CLL patient specimens harboring various mutational and cytogenetic backgrounds, including categories of high-risk. These data highlight the unique potential of irreversible menin inhibition as a novel therapeutic option for patients with CLL.