Therapeutic destruction of insulin receptor substrates for cancer treatment.
Therapeutic destruction of insulin receptor substrates for cancer treatment.
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DOI：
10.1158/0008-5472.can-12-3385
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发表时间：
2013-07-15
期刊：
影响因子：
11.2
通讯作者：
Levitzki A
中科院分区：
文献类型：
--
作者：
Reuveni H;Flashner-Abramson E;Steiner L;Makedonski K;Song R;Shir A;Herlyn M;Bar-Eli M;Levitzki A
胰岛素受体底物1和2 （IRS1/2）介导胰岛素样生长因子1受体（IGF1R）、胰岛素受体（IR）和其他癌蛋白的有丝分裂和抗凋亡信号。IRS1在癌细胞增殖中起核心作用，其表达在许多人类恶性肿瘤中增加，其上调介导对抗癌药物的耐药性。IRS2与癌细胞运动和转移有关。目前还没有针对IRS1/2的抗癌药物。我们提出了新的IGF1R/ irs靶向药物（NT化合物），促进抑制丝氨酸磷酸化和IRS1和IRS2的降解。IRS1/2的消除导致IRS1/2介导的信号传导的长期抑制。在揭示对B-RAFV600E/K抑制剂耐药的新机制的同时，这种抑制在癌细胞中的治疗意义得到了证明。我们发现，在PLX4032耐药的黑色素瘤细胞和来自PLX4032耐药患者的细胞系中，IRS1表达上调。在这两种情况下，NT化合物导致IRS蛋白的消除并诱发细胞死亡。体内用NT化合物治疗可显著抑制plx4032耐药肿瘤的生长，并在卵巢癌和前列腺癌中显示出强大的抗肿瘤作用。我们的研究结果为IRS1/2抑制剂作为癌症治疗的概念提供了临床前证据，包括plx4032耐药黑色素瘤。通过消除IRS蛋白，这些药物应该可以防止获得对突变b - raf抑制剂的耐药性，并可能恢复耐药肿瘤的药物敏感性。
Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and anti-apoptotic signaling from insulin-like growth factor 1 receptor (IGF1R), insulin receptor (IR) and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies and its up-regulation mediates resistance to anti-cancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently there are no anti-cancer agents that target IRS1/2. We present new IGF1R/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was demonstrated while unraveling a novel mechanism of resistance to B-RAFV600E/K inhibitors. We found that IRS1 is up-regulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors, and displayed potent anti-tumor effects in ovarian and prostate cancers. Our findings offer preclinical proof of concept for IRS1/2 inhibitors as cancer therapeutics including in PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors.