Irreversible HER2 inhibitors overcome resistance to the RSL3 ferroptosis inducer in non-HER2 amplified luminal breast cancer.
Irreversible HER2 inhibitors overcome resistance to the RSL3 ferroptosis inducer in non-HER2 amplified luminal breast cancer.
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DOI：
10.1038/s41419-023-06042-1
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发表时间：
2023-08-18
影响因子：
9
通讯作者：
Mills, Gordon B.
中科院分区：
文献类型：
--
作者：
Park, Soon Young;Jeong, Kang Jin;Poire, Alfonso;Zhang, Dong;Tsang, Yiu Huen;Blucher, Aurora S.;Mills, Gordon B.
铁下垂是一种程序性细胞死亡，可被XCT转运蛋白(Erastin)或Gpx4(RSL3)的抑制剂促进。我们发现Gpx4，而不是XCT转运蛋白，在管腔性乳腺癌中选择性升高。与这一观察结果一致的是，大多数腔内乳腺癌细胞系对RSL3非常敏感，而对Erastin的敏感性有限。在对RSL3耐药但不敏感的乳腺癌细胞系中，RSL3诱导HER2通路激活。不可逆的HER2抑制剂，包括neratinib，逆转了RSL3耐药细胞系的RSL3耐药性。RSL3和Neratinib联合治疗通过线粒体铁依赖的活性氧产生和脂质过氧化增加铁下垂。RSL3还激活了复制应激，伴随着S期和G2/M期的阻滞，导致了对靶向DNA损伤检查点的敏感性。总之，我们的数据支持RSL3与不可逆转的HER2抑制剂在临床试验中的联合应用。
Ferroptosis, a form of programed cell death, can be promoted by inhibitors of the xCT transporter (erastin) or GPX4 (RSL3). We found that GPX4, but not the xCT transporter, is selectively elevated in luminal breast cancer. Consistent with this observation, the majority of luminal breast cancer cell lines are exquisitely sensitive to RSL3 with limited sensitivity to erastin. In RSL3-resistant, but not sensitive, luminal breast cancer cell lines, RSL3 induces HER2 pathway activation. Irreversible HER2 inhibitors including neratinib reversed RSL3 resistance in constitutively RSL3-resistant cell lines. Combination treatment with RSL3 and neratinib increases ferroptosis through mitochondrial iron-dependent reactive oxygen species production and lipid peroxidation. RSL3 also activated replication stress and concomitant S phase and G2/M blockade leading to sensitivity to targeting the DNA damage checkpoint. Together, our data support the exploration of RSL3 combined with irreversible HER2 inhibitors in clinical trials.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
DOI：
10.1038/s41568-022-00454-5
发表时间：
2022-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
7
作者：
Mertins, Philipp;Yang, Feng;Carr, Steven A.
通讯作者：
Carr, Steven A.
影响因子：
50.3
作者：
Neve, Richard M.;Chin, Koei;Gray, Joe W.
通讯作者：
Gray, Joe W.
影响因子：
44.1
作者：
Lei, Guang;Zhang, Yilei;Gan, Boyi
通讯作者：
Gan, Boyi