Okkenhaug Klaus, Graupera Mariona, Vanhaesebroeck Bart
Laboratory of Lymphocyte Signalling and Development, The Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom.
Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
Cancer Discov. 2016 Oct;6(10):1090-1105. doi: 10.1158/2159-8290.CD-16-0716. Epub 2016 Sep 21.
The PI3K pathway is hyperactivated in most cancers, yet the capacity of PI3K inhibitors to induce tumor cell death is limited. The efficacy of PI3K inhibition can also derive from interference with the cancer cells' ability to respond to stromal signals, as illustrated by the approved PI3Kδ inhibitor idelalisib in B-cell malignancies. Inhibition of the leukocyte-enriched PI3Kδ or PI3Kγ may unleash antitumor T-cell responses by inhibiting regulatory T cells and immune-suppressive myeloid cells. Moreover, tumor angiogenesis may be targeted by PI3K inhibitors to enhance cancer therapy. Future work should therefore also explore the effects of PI3K inhibitors on the tumor stroma, in addition to their cancer cell-intrinsic impact.
The PI3K pathway extends beyond the direct regulation of cancer cell proliferation and survival. In B-cell malignancies, targeting PI3K purges the tumor cells from their protective microenvironment. Moreover, we propose that PI3K isoform-selective inhibitors may be exploited in the context of cancer immunotherapy and by targeting angiogenesis to improve drug and immune cell delivery. Cancer Discov; 6(10); 1090-105. ©2016 AACR.
PI3K通路在大多数癌症中被过度激活，但PI3K抑制剂诱导肿瘤细胞死亡的能力有限。PI3K抑制的疗效也可源于干扰癌细胞对基质信号的反应能力，如已获批的PI3Kδ抑制剂idelalisib在B细胞恶性肿瘤中的表现。抑制富含白细胞的PI3Kδ或PI3Kγ可能通过抑制调节性T细胞和免疫抑制性髓样细胞来释放抗肿瘤T细胞反应。此外，PI3K抑制剂可靶向肿瘤血管生成以增强癌症治疗效果。因此，未来的研究除了探索PI3K抑制剂对癌细胞内在的影响外，还应研究其对肿瘤基质的作用。
PI3K通路不仅直接调控癌细胞的增殖和存活。在B细胞恶性肿瘤中，靶向PI3K可将肿瘤细胞从其保护性微环境中清除。此外，我们提出PI3K亚型选择性抑制剂可用于癌症免疫治疗，并通过靶向血管生成来改善药物和免疫细胞的递送。癌症发现；6(10)；1090 - 105。©2016美国癌症研究协会。
