Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy.
Molecular Pathways and Mechanisms of TGFβ in Cancer Therapy.
复制标题
DOI：
10.1158/1078-0432.ccr-21-3750
复制
发表时间：
2023-06-01
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
尽管一些抑制转化生长因子β (tgf - β)的药物正在癌症患者中进行测试，但tgf - β抑制的临床益处尚未实现。tgf - β致蛋白的无数机制可能是其有效部署的关键障碍；癌细胞经常使用tgf - β调节程序，产生可塑性，使肿瘤微环境变得宽松，并严重抑制免疫识别，这是目前大多数tgf - β抑制剂早期试验的目标。在这里，我们讨论了TGFβ生物学调节DNA修复的一个不太为人所知的方面，介导对放疗和化疗的反应。在具有tgf - β信号传导能力的癌症中，tgf - β促进有效的DNA修复并抑制易出错的修复，从而赋予对基因毒性治疗的抗性并限制肿瘤控制。TGFβ信号内在受损的癌症对标准的基因毒性治疗更有反应。认识到TGFβ是DNA修复和免疫抑制的关键调节因子，可能用于协同基因毒性治疗和免疫治疗的组合，以使癌症患者受益。
Even though a cadre of agents that inhibit transforming growth factor β (TGFβ) is being tested in cancer patients, clinical benefit from TGFβ inhibition has not yet been achieved. The myriad mechanisms in which TGFβ is protumorigenic may be a key obstacle to its effective deployment; cancer cells frequently employ TGFβ-regulated programs that engender plasticity, enable a permissive tumor microenvironment, and profoundly suppress immune recognition, which is the target of most current early-phase trials of TGFβ inhibitors. Here we discuss the implications of a less well-recognized aspect of TGFβ biology regulating DNA repair that mediates responses to radiation and chemotherapy. In cancers that are TGFβ signaling-competent, TGFβ promotes effective DNA repair and suppresses error-prone repair, thus conferring resistance to genotoxic therapies and limiting tumor control. Cancers in which TGFβ signaling is intrinsically compromised are more responsive to standard genotoxic therapy. Recognition that TGFβ is a key moderator of both DNA repair and immunosuppression might be used to synergize combinations of genotoxic therapy and immunotherapy to benefit cancer patients.