Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.
Focal Adhesion Kinase Provides a Collateral Vulnerability That Can Be Leveraged to Improve mTORC1 Inhibitor Efficacy.
复制标题
局灶性粘附激酶提供了可以利用的侧支脆弱性，以提高MTORC1抑制剂功效。
DOI：
10.3390/cancers14143374
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发表时间：
2022-07-11
期刊：
影响因子：
5.2
通讯作者：
Keri, Ruth A.
中科院分区：
文献类型：
--
作者：
Cuellar-Vite, Leslie;Weber-Bonk, Kristen L.;Abdul-Karim, Fadi W.;Booth, Christine N.;Keri, Ruth A.
关键词：
虽然PI3K/AKT/mTORC1通路在乳腺癌中高度活跃，但mTORC1靶向药物并非对所有乳腺癌亚型都有效。为了确定潜在的耐药机制，我们利用了一种在mTORC1抑制剂雷帕霉素存在的情况下仍继续生长的乳腺癌小鼠模型。这种治疗导致了控制肿瘤细胞周围环境（细胞外基质或ECM）的基因活性发生变化。为了确定ECM是否能调节mTORC1抑制剂的有效性，我们靶向粘着斑激酶（FAK），这是一种介导从ECM到细胞内信号传导的必需蛋白质。在对mTORC1抑制剂相对耐药的模型中，阻断FAK提高了mTORC1抑制剂抑制肿瘤生长的能力。然而，在对mTORC1抑制剂敏感的模型中，抑制FAK没有效果。这些结果提供了临床前证据，表明FAK和mTORC1的双重靶向可能会提高对mTORC1抑制剂耐药的癌症的治疗效果。
PI3K/AKT/mTORC1通路是许多癌症，特别是乳腺癌的一个主要治疗靶点。依维莫司是一种用于转移性雌激素受体阳性（ER +）和表皮生长因子受体2阴性（HER2 -）乳腺癌的mTORC1抑制剂。然而，mTORC1抑制剂在其他乳腺癌亚型中疗效有限。我们试图发现对mTORC1抑制的协同敏感性，以便利用其来提高治疗反应。利用一种对mTORC1抑制具有内在耐药性的乳腺癌小鼠模型，我们发现雷帕霉素改变了许多细胞外基质基因的表达，这表明整合素/FAK在控制mTORC1抑制剂疗效方面可能具有潜在作用。在乳腺癌细胞系中，FAK的激活也与雷帕霉素的反应呈负相关。支持其在患者中的潜在效用的是，在超过50%的人类乳腺癌中观察到了FAK的激活。虽然在对雷帕霉素高度敏感的乳腺癌小鼠模型中阻断FAK对肿瘤生长没有影响，但抑制FAK使对雷帕霉素耐药的肿瘤对mTORC1抑制敏感。这些数据揭示了当对mTORC1抑制剂耐药的肿瘤中mTORC1信号缺失时，对FAK存在一种内在的依赖性。它们还提出了一种通过抑制FAK信号来提高mTORC1抑制剂在耐药癌症中疗效的精准医疗方法。
While the PI3K/AKT/mTORC1 pathway is highly active in breast cancer, mTORC1-targeting drugs are not effective in all breast cancer subtypes. To identify potential resistance mechanisms, we utilized a mouse model of breast cancer that continues to grow in the presence of the mTORC1 inhibitor, rapamycin. This treatment caused changes in the activity of genes that control the environment surrounding the tumor cells (the extracellular matrix or ECM). To determine if the ECM can modulate mTORC1 inhibitor effectiveness, we targeted focal adhesion kinase (FAK), an integral protein that mediates signaling from the ECM into the cell. In models that are relatively resistant to mTORC1 inhibitors, blocking FAK improved the ability of mTORC1 inhibitors to suppress tumor growth. However, in models that are sensitive to mTORC1 inhibitors, FAK suppression had no effect. These results provide preclinical evidence that the dual targeting of FAK and mTORC1 may improve therapeutic impact in cancers that are resistant to mTORC1 inhibitors. The PI3K/AKT/mTORC1 pathway is a major therapeutic target for many cancers, particularly breast cancer. Everolimus is an mTORC1 inhibitor used in metastatic estrogen receptor-positive (ER+) and epidermal growth factor receptor 2-negative (HER2-) breast cancer. However, mTORC1 inhibitors have limited efficacy in other breast cancer subtypes. We sought to discover collateral sensitivities to mTORC1 inhibition that could be exploited to improve therapeutic response. Using a mouse model of breast cancer that is intrinsically resistant to mTORC1 inhibition, we found that rapamycin alters the expression of numerous extracellular matrix genes, suggesting a potential role for integrins/FAK in controlling mTORC1-inhibitor efficacy. FAK activation was also inversely correlated with rapamycin response in breast cancer cell lines. Supporting its potential utility in patients, FAK activation was observed in >50% of human breast cancers. While blocking FAK in mouse models of breast cancer that are highly responsive to rapamycin had no impact on tumor growth, FAK inhibition sensitized rapamycin-resistant tumors to mTORC1 inhibition. These data reveal an innate dependency on FAK when mTORC1 signaling is lost in tumors that are resistant to mTORC1 inhibitors. They also suggest a precision medicine approach to improving mTORC1 inhibitor efficacy in resistant cancers by suppressing FAK signaling.
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影响因子：
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影响因子：
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