Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
Program in Cancer Biology, Stanford University School of Medicine, Stanford, California, USA.
Nat Med. 2013 May;19(5):626-630. doi: 10.1038/nm.3165. Epub 2013 Apr 21.
Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals. Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction. Furthermore, recently identified ERK1/2-inducing mutations in MEK1 and MEK2 (MEK1/2) MAPK genes in melanoma confer resistance to emerging therapeutic MEK inhibitors, underscoring the challenges facing direct kinase inhibition in cancer. MAPK scaffolds, such as IQ motif-containing GTPase activating protein 1 (IQGAP1), assemble pathway kinases to affect signal transmission, and disrupting scaffold function therefore offers an orthogonal approach to MAPK cascade inhibition. Consistent with this, we found a requirement for IQGAP1 in RAS-driven tumorigenesis in mouse and human tissue. In addition, the ERK1/2-binding IQGAP1 WW domain peptide disrupted IQGAP1-ERK1/2 interactions, inhibited RAS- and RAF-driven tumorigenesis, bypassed acquired resistance to the BRAF inhibitor vemurafenib (PLX-4032) and acted as a systemically deliverable therapeutic to significantly increase the lifespan of tumor-bearing mice. Scaffold-kinase interaction blockade acts by a mechanism distinct from direct kinase inhibition and may be a strategy to target overactive oncogenic kinase cascades in cancer.
ERK1 和 ERK2（ERK1/2）MAP 激酶（MAPK）级联在超过 30%的癌症中上调，通常通过受体酪氨酸激酶或其他上游基因（包括 KRAS 和 BRAF）的突变激活。靶向内源性 MAPK 的努力受到这些激酶在哺乳动物中对生存至关重要的事实的挑战。此外，新的 BRAF 突变体抑制剂的有效性已通过选择 BRAF 独立的 ERK1/2 诱导机制而降低。此外，最近在黑色素瘤中的 MEK1 和 MEK2（MEK1/2）MAPK 基因中发现的 ERK1/2 诱导突变赋予了对新兴治疗性 MEK 抑制剂的耐药性，突显了直接激酶抑制在癌症中面临的挑战。MAPK 支架，如 IQ 基序包含的 GTP 酶激活蛋白 1（IQGAP1），组装途径激酶以影响信号转导，因此破坏支架功能提供了一种与 MAPK 级联抑制正交的方法。与这一致，我们发现 IQGAP1 在 RAS 驱动的小鼠和人类组织中的肿瘤发生中是必需的。此外，ERK1/2 结合的 IQGAP1 WW 结构域肽破坏了 IQGAP1-ERK1/2 相互作用，抑制了 RAS 和 RAF 驱动的肿瘤发生，绕过了对 BRAF 抑制剂 vemurafenib（PLX-4032）的获得性耐药，并作为一种可系统递送至的治疗药物，显著延长了荷瘤小鼠的寿命。支架激酶相互作用阻断作用通过与直接激酶抑制不同的机制起作用，并且可能是靶向癌症中过度活跃的致癌激酶级联的一种策略。
