Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition
Increased lysosomal biomass is responsible for the resistance of triple-negative breast cancers to CDK4/6 inhibition
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DOI：
10.1126/sciadv.abb2210
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发表时间：
2020-06-01
期刊：
影响因子：
13.6
通讯作者：
Sicinski, Piotr
中科院分区：
文献类型：
--
作者：
Fassl, Anne;Brain, Christopher;Sicinski, Piotr
细胞周期蛋白依赖性激酶CDK 4和CDK 6的抑制剂已被批准用于治疗激素受体阳性乳腺癌。相反，三阴性乳腺癌（TNBC）对CDK 4/6抑制具有抗性。在这里，我们证明了TNBC的一个亚组非常需要CDK 4/6用于增殖，然而，由于CDK 4/6抑制剂被隔离到肿瘤细胞溶酶体中，这些TNBC对CDK 4/6抑制具有抗性。这种隔离是由TNBC细胞中增强的溶酶体生物合成和增加的溶酶体数量引起的。我们开发了新的CDK 4/6抑制剂化合物，其逃避溶酶体螯合并且对抗性TNBC有效。我们还表明，共同管理的lysosomotropic或溶酶体不稳定的化合物（抗生素阿奇霉素，抗抑郁药siramesine，抗疟化合物氯喹）呈现耐药肿瘤细胞敏感，目前使用的CDK 4/6抑制剂。最后，CDK 2的共抑制阻止了CDK 4/6受体抗性细胞的增殖。这些观察结果可能将CDK 4/6抑制剂的使用扩展到对当前抗CDK 4/6疗法难治的TNBC。
Inhibitors of cyclin-dependent kinases CDK4 and CDK6 have been approved for treatment of hormone receptor-positive breast cancers. In contrast, triple-negative breast cancers (TNBCs) are resistant to CDK4/6 inhibition. Here, we demonstrate that a subset of TNBC critically requires CDK4/6 for proliferation, and yet, these TNBC are resistant to CDK4/6 inhibition due to sequestration of CDK4/6 inhibitors into tumor cell lysosomes. This sequestration is caused by enhanced lysosomal biogenesis and increased lysosomal numbers in TNBC cells. We developed new CDK4/6 inhibitor compounds that evade the lysosomal sequestration and are efficacious against resistant TNBC. We also show that coadministration of lysosomotropic or lysosome-destabilizing compounds (an antibiotic azithromycin, an antidepressant siramesine, an antimalaria compound chloroquine) renders resistant tumor cells sensitive to currently used CDK4/6 inhibitors. Lastly, coinhibition of CDK2 arrested proliferation of CDK4/6 inhibitor-resistant cells. These observations may extend the use of CDK4/6 inhibitors to TNBCs that are refractory to current anti-CDK4/6 therapies.