CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor.
CD44/HA signaling mediates acquired resistance to a PI3Kα inhibitor.
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CD44/HA 信号传导介导对 PI3Kα 抑制剂的获得性耐药
DOI：
10.1038/s41419-020-03037-0
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发表时间：
2020-10-06
影响因子：
9
通讯作者：
Gao F
中科院分区：
文献类型：
--
作者：
Yang C;Sheng Y;Shi X;Liu Y;He Y;Du Y;Zhang G;Gao F
大多数携带PIK 3CA突变的管腔型乳腺癌（BrCas）最初对磷酸肌醇-3-激酶（PI 3 K）-α抑制剂有反应，但许多最终变得耐药。这种抵抗的潜在机制仍然不清楚。在这项工作中，我们发现由于异常同种型剪接导致的CD 44高状态是从管腔型BrCas对PI 3 K α抑制剂（BLY 719）的适应性耐药性中获得的。值得注意的是，在PIK 3CA突变型乳腺癌中，CD 44的表达与雌激素受体（ER）活性呈正相关，而PI 3 K α通路抑制后的ER依赖性转录反过来又由CD 44介导。此外，CD 44与配体透明质酸（HA）的相互作用启动了Src-ERK信号级联反应，随后在PI 3 K α抑制剂存在下维持了AKT和mTOR活性。通过破坏CD 44/HA相互作用阻止了该途径的激活，这反过来又恢复了对BLY 719的敏感性。我们的研究结果表明，ER-CD 44-HA信号通路介导Src-ERK信号级联的强代偿性激活，可能有助于PI 3 K α抑制剂获得性耐药的发展。本研究为PI 3 K α抑制治疗的适应性抵抗机制提供了新的见解。
Most luminal breast carcinomas (BrCas) bearing PIK3CA mutations initially respond to phosphoinositide-3-kinase (PI3K)-α inhibitors, but many eventually become resistant. The underlying mechanisms of this resistance remain obscure. In this work, we showed that a CD44high state due to aberrant isoform splicing was acquired from adaptive resistance to a PI3Kα inhibitor (BLY719) in luminal BrCas. Notably, the expression of CD44 was positively correlated with estrogen receptor (ER) activity in PIK3CA-mutant breast cancers, and ER-dependent transcription upon PI3Kα pathway inhibition was in turn mediated by CD44. Furthermore, the interaction of CD44 with the ligand hyaluronan (HA) initiated the Src-ERK signaling cascade, which subsequently maintained AKT and mTOR activity in the presence of a PI3Kα inhibitor. Activation of this pathway was prevented by disruption of the CD44/HA interaction, which in turn restored sensitivity to BLY719. Our results revealed that an ER-CD44-HA signaling circuit that mediates robust compensatory activation of the Src-ERK signaling cascade may contribute to the development of acquired resistance to PI3Kα inhibitors. This study provides new insight into the mechanism of adaptive resistance to PI3Kα inhibition therapy.