PDF(Pubmed)
Abstract：
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 mTORS2035T 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.
摘要：
mTORC1在肾细胞癌（RCC）中异常激活，并被rapalogs靶向。至于其他靶向治疗，rapalogs的临床应用受到耐药性发展的限制。抗性通常由目标突变引起，但mTOR突变在RCC中很少发现。和人类一样,延长RCC肿瘤移植物（TG）的rapalog治疗导致耐药性。出乎意料的是,抗性肿瘤的外植体在小鼠的培养和随后的移植中均变得敏感。值得注意的是,尽管肿瘤细胞中存在持续的mTORC1抑制，但仍出现耐药性。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，我们设计了具有抗性mTOR突变(S2035T)的免疫受损受体小鼠。有趣的是,在mTORS2035T小鼠中，TG对rapalogs产生抗性。尽管肿瘤细胞中存在mTORC1抑制，但仍存在耐药性，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mTORC1的强制激活足以赋予rapalogs抗性。这些研究强调了非肿瘤细胞中mTORC1抑制对rapalog抗肿瘤活性的重要性，并为RCC患者缺乏mTOR抗性突变提供了解释。
