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Activating KRAS, NRAS, and BRAF mutants enhance proteasome capacity and reduce endoplasmic reticulum stress in multiple myeloma.
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2020-08-18 , DOI: 10.1073/pnas.2005052117
Fazal Shirazi 1 , Richard J Jones 1 , Ram K Singh 1 , Jianxuan Zou 1 , Isere Kuiatse 1 , Zuzana Berkova 1 , Hua Wang 1 , Hans C Lee 1 , Samuel Hong 1 , Larry Dick 2 , Nibedita Chattopadhyay 2 , Robert Z Orlowski 3, 4
Affiliation  

KRAS, NRAS, and BRAF mutations which activate p44/42 mitogen-activated protein kinase (MAPK) signaling are found in half of myeloma patients and contribute to proteasome inhibitor (PI) resistance, but the underlying mechanisms are not fully understood. We established myeloma cell lines expressing wild-type (WT), constitutively active (CA) (G12V/G13D/Q61H), or dominant-negative (DN) (S17N)-KRAS and -NRAS, or BRAF-V600E. Cells expressing CA mutants showed increased proteasome maturation protein (POMP) and nuclear factor (erythroid-derived 2)-like 2 (NRF2) expression. This correlated with an increase in catalytically active proteasome subunit β (PSMB)-8, PSMB9, and PSMB10, which occurred in an ETS transcription factor-dependent manner. Proteasome chymotrypsin-like, trypsin-like, and caspase-like activities were increased, and this enhanced capacity reduced PI sensitivity, while DN-KRAS and DN-NRAS did the opposite. Pharmacologic RAF or MAPK kinase (MEK) inhibitors decreased proteasome activity, and sensitized myeloma cells to PIs. CA-KRAS, CA-NRAS, and CA-BRAF down-regulated expression of endoplasmic reticulum (ER) stress proteins, and reduced unfolded protein response activation, while DN mutations increased both. Finally, a bortezomib (BTZ)/MEK inhibitor combination showed enhanced activity in vivo specifically in CA-NRAS models. Taken together, the data support the hypothesis that activating MAPK pathway mutations enhance PI resistance by increasing proteasome capacity, and provide a rationale for targeting such patients with PI/RAF or PI/MEK inhibitor combinations. Moreover, they argue these mutations promote myeloma survival by reducing cellular stress, thereby distancing plasma cells from the apoptotic threshold, potentially explaining their high frequency in myeloma.



中文翻译:

激活KRAS,NRAS和BRAF突变体可增强蛋白酶体能力并减少多发性骨髓瘤中的内质网应激。

在一半的骨髓瘤患者中发现了激活p44 / 42丝裂原活化蛋白激酶(MAPK)信号转导的KRASNRASBRAF突变,这些突变有助于蛋白酶体抑制剂(PI)的耐药性,但其潜在机制尚不完全清楚。我们建立了表达野生型(WT),组成型活性(CA)(G12V / G13D / Q61H),或显性负(DN)骨髓瘤细胞系(S17N) - KRAS和- NRASBRAF-V600E。表达CA突变体的细胞显示蛋白酶体成熟蛋白(POMP)和核因子(类胡萝卜素2)样2(NRF2)表达增加。这与以ETS转录因子依赖性方式发生的催化活性蛋白酶体亚基β(PSMB)-8,PSMB9和PSMB10的增加有关。蛋白酶体胰凝乳蛋白酶样,胰蛋白酶样和半胱天冬酶样活性增加,这种增强的能力降低了PI敏感性,而DN- KRAS和DN- NRAS则相反。药理学上的RAF或MAPK激酶(MEK)抑制剂降低了蛋白酶体的活性,并使骨髓瘤细胞对PI敏感。CA- KRAS,CA- NRAS和CA- BRAF下调内质网(ER)应激蛋白的表达,并减少未折叠的蛋白应答激活,而DN突变均增加。最后,硼替佐米(BTZ)/ MEK抑制剂组合特别在CA- NRAS模型中显示出增强的体内活性。综上所述,数据支持以下假设:激活MAPK途径突变可通过增加蛋白酶体容量来增强PI抵抗力,并为针对此类患者使用PI / RAF或PI / MEK抑制剂组合提供依据。此外,他们认为这些突变通过降低细胞压力从而使浆细胞与凋亡阈值区分开来促进骨髓瘤的存活,从而可能解释了其在骨髓瘤中的高频率。

更新日期:2020-08-19
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