Kidney Cancer Program, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852.
Hematology-Oncology Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8852.
Proc Natl Acad Sci U S A. 2024 Jun 18;121(25):e2310793121. doi: 10.1073/pnas.2310793121. Epub 2024 Jun 11.
mTORC1 is aberrantly activated in renal cell carcinoma (RCC) and is targeted by rapalogs. As for other targeted therapies, rapalogs clinical utility is limited by the development of resistance. Resistance often results from target mutation, but mTOR mutations are rarely found in RCC. As in humans, prolonged rapalog treatment of RCC tumorgrafts (TGs) led to resistance. Unexpectedly, explants from resistant tumors became sensitive both in culture and in subsequent transplants in mice. Notably, resistance developed despite persistent mTORC1 inhibition in tumor cells. In contrast, mTORC1 became reactivated in the tumor microenvironment (TME). To test the role of the TME, we engineered immunocompromised recipient mice with a resistance mTOR mutation (S2035T). Interestingly, TGs became resistant to rapalogs in mTOR mice. Resistance occurred despite mTORC1 inhibition in tumor cells and could be induced by coculturing tumor cells with mutant fibroblasts. Thus, enforced mTORC1 activation in the TME is sufficient to confer resistance to rapalogs. These studies highlight the importance of mTORC1 inhibition in nontumor cells for rapalog antitumor activity and provide an explanation for the lack of mTOR resistance mutations in RCC patients.
mTORC1 在肾细胞癌（RCC）中异常激活，并被 rapamycin 靶向。与其他靶向治疗一样，rapamycin 的临床应用受到耐药性的限制。耐药性通常是由于靶标突变引起的，但在 RCC 中很少发现 mTOR 突变。与人类一样，RCC 肿瘤移植物（TG）的长期 rapamycin 治疗导致了耐药性。出乎意料的是，来自耐药肿瘤的外植体在培养中和随后在小鼠中的移植中都变得敏感。值得注意的是，尽管肿瘤细胞中持续存在 mTORC1 抑制，但耐药性还是发展了。相比之下，mTORC1 在肿瘤微环境（TME）中重新激活。为了测试 TME 的作用，我们使用具有耐药性 mTOR 突变（S2035T）的免疫缺陷受体小鼠来设计工程化肿瘤。有趣的是，在 mTOR 小鼠中，TG 对 rapamycin 产生了耐药性。尽管肿瘤细胞中存在 mTORC1 抑制，但耐药性仍然发生，并且可以通过将肿瘤细胞与突变成纤维细胞共培养来诱导。因此，TME 中强制激活 mTORC1 足以赋予对 rapamycin 的耐药性。这些研究强调了 mTORC1 在非肿瘤细胞中抑制对 rapamycin 抗肿瘤活性的重要性，并为 RCC 患者缺乏 mTOR 耐药性突变提供了解释。
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