MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer.
MAPK Reliance via Acquired CDK4/6 Inhibitor Resistance in Cancer.
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DOI：
10.1158/1078-0432.ccr-18-0410
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发表时间：
2018-09-01
期刊：
影响因子：
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通讯作者：
Knudsen KE
中科院分区：
文献类型：
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作者：
de Leeuw R;McNair C;Schiewer MJ;Neupane NP;Brand LJ;Augello MA;Li Z;Cheng LC;Yoshida A;Courtney SM;Hazard ES;Hardiman G;Hussain MH;Diehl JA;Drake JM;Kelly WK;Knudsen KE
细胞周期控制的丧失是癌症的标志，可以用药物靶向癌症，包括细胞周期蛋白依赖性激酶-4/6（CDK 4/6）激酶抑制剂，其通过维持视网膜母细胞瘤肿瘤抑制因子（RB）的活性来影响G1-S细胞周期检查点。这类药物正在对各种实体瘤类型进行临床研究，最近已被FDA批准用于治疗乳腺癌。然而，治疗耐药性的发展并不罕见。在本研究中，在早期RB阳性癌症模型中建立了palbociclib（一种CDK 4/6抑制剂）耐药性。这项研究表明，获得性palbociclib耐药性使癌细胞对CDK 4/6抑制剂具有广泛耐药性。获得性耐药与体外和体内侵袭性表型相关，包括增殖、迁移和侵袭。RNA测序分析和磷酸化蛋白质组学分析的整合揭示了激酶组的重新布线，在所有耐药模型中具有增强的MAPK信号传导的强烈富集，这导致了侵袭性的体外和体内表型和促转移信号传导。然而，CDK 4/6抑制剂抗性模型对MEK抑制剂敏感，揭示了依赖于活性MAPK信号传导来促进肿瘤细胞生长和侵袭。总之，这些研究鉴定了促进侵袭性疾病的获得性CDK 4/6抑制剂抗性中的MAPK依赖性，同时提名MEK抑制作为治疗或预防癌症中CDK 4/6抑制剂抗性的推定的新型治疗策略。
Loss of cell cycle control is a hallmark of cancer, which can be targeted with agents, including Cyclin Dependent Kinase-4/6 (CDK4/6) kinase inhibitors that impinge upon the G1-S cell cycle checkpoint via maintaining activity of the retinoblastoma tumor suppressor (RB). This class of drugs is under clinical investigation for various solid tumor types, and has recently been FDA-approved for treatment of breast cancer. However, development of therapeutic resistance is not uncommon. In this study, palbociclib (a CDK4/6 inhibitor) resistance was established in models of early stage, RB-positive cancer. This study demonstrates that acquired palbociclib resistance renders cancer cells broadly resistant to CDK4/6 inhibitors. Acquired resistance was associated with aggressive in vitro and in vivo phenotypes, including proliferation, migration, and invasion. Integration of RNA sequencing analysis and phospho-proteomics profiling revealed rewiring of the kinome, with a strong enrichment for enhanced MAPK signaling across all resistance models, which resulted in aggressive in vitro and in vivo phenotypes and pro-metastatic signaling. However, CDK4/6 inhibitor resistant models were sensitized to MEK inhibitors, revealing reliance on active MAPK signaling to promote tumor cell growth and invasion. In sum, these studies identify MAPK reliance in acquired CDK4/6 inhibitor resistance that promotes aggressive disease, while nominating MEK inhibition as putative novel therapeutic strategy to treat or prevent CDK4/6 inhibitor resistance in cancer.