The clinical efficiency of everolimus, an mammalian target of rapamycin (mTOR) inhibitor, is palliative as sequential or second-line therapy for renal cell carcinoma (RCC). However, the limited response of everolimus in RCC remains uncertain. In the present study, everolimus-resistant RCC models were established to understand the mechanisms and to seek combination approaches. Consequently, the activation of ERK was found to contribute toward everolimus-acquired resistance and poor prognosis in patients with RCC. In addition, the efficacy and mechanism of combination treatment underlying RCC using everolimus and ERK inhibitors was investigated. The ERK inhibitor in combination with everolimus synergistically inhibited the proliferation of RCC cells by arresting the cell cycle in the G1 phase. The combination treatment markedly attenuated the deoxyribonucleoside triphosphate (dNTP) pools by downregulating the mRNA expression of RRM1 and RRM2 through E2F1. The overexpression of E2F1 or supplementation of dNTP rescued the anti-proliferation activity of the everolimus-SCH772984 combination. The antitumor efficacy of combination therapy was reiterated in RCC xenograft models. Thus, the current findings provided evidence that the everolimus-ERK inhibitor combination is a preclinical therapeutic strategy for RCC.

依维莫司是雷帕霉素（mTOR）抑制剂的哺乳动物靶点，其临床疗效可作为肾细胞癌（RCC）的序贯治疗或二线治疗而治标不治本。然而，依维莫司在RCC中的有限反应仍不确定。在本研究中，建立了抗依维莫司的RCC模型，以了解其机理并寻求组合方法。因此，发现ERC的激活可导致RCC患者依维莫司获得性耐药和预后不良。此外，还研究了使用依维莫司和ERK抑制剂联合治疗RCC的疗效和机理。ERK抑制剂与依维莫司合用可通过将细胞周期停滞在G1期来协同抑制RCC细胞的增殖。RRM1和RRM2到E2F1。E2F1的过量表达或dNTP的补充挽救了依维莫司-SCH772984组合的抗增殖活性。在RCC异种移植模型中重申了联合疗法的抗肿瘤功效。因此，目前的发现提供了证据，依维莫司-ERK抑制剂组合是RCC的临床前治疗策略。