Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Harvard Medical School, Boston, MA 02215, USA; CHU de Clermont-Ferrand, 63000 Clermont-Ferrand, France; Université Clermont Auvergne, EA7453 CHELTER, 63000 Clermont-Ferrand, France.
Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Dana Building, Room DA-520, Boston MA 02215-02115, USA; Harvard Medical School, Boston, MA 02215, USA.
Cancer Cell. 2019 Oct 14;36(4):369-384.e13. doi: 10.1016/j.ccell.2019.08.005. Epub 2019 Sep 19.
Mitochondrial apoptosis can be effectively targeted in lymphoid malignancies with the FDA-approved B cell lymphoma 2 (BCL-2) inhibitor venetoclax, but resistance to this agent is emerging. We show that venetoclax resistance in chronic lymphocytic leukemia is associated with complex clonal shifts. To identify determinants of resistance, we conducted parallel genome-scale screens of the BCL-2-driven OCI-Ly1 lymphoma cell line after venetoclax exposure along with integrated expression profiling and functional characterization of drug-resistant and engineered cell lines. We identified regulators of lymphoid transcription and cellular energy metabolism as drivers of venetoclax resistance in addition to the known involvement by BCL-2 family members, which were confirmed in patient samples. Our data support the implementation of combinatorial therapy with metabolic modulators to address venetoclax resistance.
线粒体凋亡可以通过美国食品和药物管理局批准的 B 细胞淋巴瘤 2 (BCL-2) 抑制剂 venetoclax 有效地靶向治疗淋巴恶性肿瘤，但这种药物的耐药性正在出现。我们表明，慢性淋巴细胞白血病对 venetoclax 的耐药性与复杂的克隆转移有关。为了确定耐药性的决定因素，我们在 venetoclax 暴露后，对 BCL-2 驱动的 OCI-Ly1 淋巴瘤细胞系进行了平行的基因组规模筛选，同时对耐药性和工程细胞系进行了整合的表达谱分析和功能特征分析。我们发现，除了已知的 BCL-2 家族成员的参与外，淋巴转录和细胞能量代谢的调节剂也是 venetoclax 耐药性的驱动因素，这在患者样本中得到了证实。我们的数据支持实施联合治疗，包括代谢调节剂，以解决 venetoclax 耐药性。
