Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.
Systematic Functional Characterization of Resistance to PI3K Inhibition in Breast Cancer.
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DOI：
10.1158/2159-8290.cd-16-0305
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发表时间：
2016-10
期刊：
影响因子：
28.2
通讯作者：
Garraway LA
中科院分区：
文献类型：
--
作者：
Le X;Antony R;Razavi P;Treacy DJ;Luo F;Ghandi M;Castel P;Scaltriti M;Baselga J;Garraway LA
PIK3CA（编码磷酸肌醇-3激酶（PI3K）α亚型）是乳腺癌中最常见的突变癌基因。小分子PI3K抑制剂已在临床试验中显示出前景;然而，内在和获得性耐药性限制了它们的效用。我们使用了一种系统性的功能获得方法来鉴定乳腺癌细胞中上调赋予对PI3K抑制剂BYL 719抗性的基因。在经验证的抗性基因中，PIM激酶通过以AKT非依赖性方式维持下游PI3K效应子活化来赋予抗性。PIM和PI3K的同时药理学抑制克服了这种耐药机制。我们还观察到在对PI3K抑制剂具有临床耐药性的乳腺癌活检组织中PIM表达和活性上调。在未经治疗的乳腺癌中，PIM1过表达与PIK3CA突变相互排斥，表明下游功能冗余。总之，这些结果提供了对PI3K抑制剂耐药性的新见解，并支持在PIK3CA突变癌症亚组中联合PIM/PI3K抑制的临床研究。
PIK3CA (which encodes the phosphoinositide-3 kinase (PI3K) alpha isoform) is the most frequently mutated oncogene in breast cancer. Small-molecule PI3K inhibitors have shown promise in clinical trials; however, intrinsic and acquired resistance limits their utility. We used a systematic gain-of-function approach to identify genes whose upregulation confers resistance to the PI3K inhibitor BYL719 in breast cancer cells. Among the validated resistance genes, PIM kinases conferred resistance by maintaining downstream PI3K effector activation in an AKT-independent manner. Concurrent pharmacological inhibition of PIM and PI3K overcame this resistance mechanism. We also observed upregulated PIM expression and activity in a subset of breast cancer biopsies with clinical resistance to PI3K inhibitors. PIM1 overexpression is mutually exclusive with PIK3CA mutation in treatment-naïve breast cancers, suggesting downstream functional redundancy. Together, these results offer new insights into resistance to PI3K inhibitors and support clinical studies of combined PIM/PI3K inhibition in a subset of PIK3CA-mutant cancers.