Inhibition of mammalian target of rapamycin complex 1 (mTORC1) with rapamycin in the absence of transforming growth factor-β (TGFβ) signaling induces apoptosis in many cancer cell lines. In the presence of TGFβ, rapamycin induces G₁ cell cycle arrest; however, in the absence of TGFβ, cells do not arrest in G₁ and progress into S-phase where rapamycin is cytotoxic rather than cytostatic. However, we observed that DU145 prostate and NCI–H2228 lung cancer cells were resistant to the cytotoxic effect of rapamycin. Of interest, the rapamycin-resistant DU145 and NCI–H2228 cells have mutations in the RB and CDKN2A tumor suppressor genes. The gene products of RB and CDKN2A (pRb and p14^ARF) suppress E2F family transcription factors that promote cell cycle progression from G₁ into S. Restoration of wild type RB or inhibition of E2F activity in DU145 and NCI–H2228 cells led to rapamycin sensitivity. These data provide evidence that the combination of mutant RB and mutant CDKN2A in cancer cells leads to rapamycin resistance, which has implications for precision medicine approaches to anti-cancer therapies.

在没有转化生长因子-β (TGFβ) 信号传导的情况下，用雷帕霉素抑制哺乳动物雷帕霉素复合物 1 (mTORC1) 可诱导许多癌细胞系发生细胞凋亡。在 TGFβ 存在的情况下，雷帕霉素诱导 G ₁细胞周期停滞；然而，在没有 TGFβ 的情况下，细胞不会停滞在 G ₁期并进入 S 期，此时雷帕霉素具有细胞毒性而不是细胞生长抑制。然而，我们观察到 DU145 前列腺和 NCI-H2228 肺癌细胞对雷帕霉素的细胞毒性作用具有抗性。有趣的是，雷帕霉素抗性 DU145 和 NCI–H2228 细胞在RB和CDKN2A肿瘤抑制基因中有突变。RB和CDKN2A的基因产物（pRb和p14^ARF ) 抑制促进细胞周期从 G ₁进入 S 的 E2F 家族转录因子。恢复野生型RB或抑制 DU145 和 NCI–H2228 细胞中的 E2F 活性导致雷帕霉素敏感性。这些数据提供的证据表明，癌细胞中突变体RB和突变体CDKN2A的结合会导致雷帕霉素耐药性，这对抗癌治疗的精准医学方法具有重要意义。