Editors' ChoiceCancer

Bringing Down the House by Targeting the Scaffold

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Science Translational Medicine  15 May 2013:
Vol. 5, Issue 185, pp. 185ec83
DOI: 10.1126/scitranslmed.3006521

A house is only as strong as its foundation—or is it? A scaffold is a structure used to support people and materials during a repair process. Knock down the scaffold, and down comes the house. Activation of Ras and mitogen-activated protein kinase (MAPK) signaling occurs in >30% of cancers, and genetic and biological evidence validate a central role for this pathway in driving tumor development and progression. Despite this, therapeutically tractable approaches to target these proteins have yet to be fully realized. Many highly selective kinase inhibitors for this nodal pathway have already been tested, with limited to no efficacy in cancer patients. As Steve Jobs said so many times, perhaps we now need to challenge the status quo and “Think different.”

Work by Jameson and colleagues has elucidated an essential role for the scaffold protein IQGAP1 in regulating MAPK signaling in a diverse range of cellular contexts. Through a series of sophisticated genetic loss-of-function experiments in mouse models, this group demonstrated a dependence of V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)–driven tumorigenesis on IQGAP1 interaction and function. Mice in which IQGAP1 had been knocked out had decreased MAPK signaling and were resistant to Hras-driven chemical carcinogenesis. Furthermore, IQGAP1 expression was increased in human KRAS-driven pancreatic ductal adenocarcinomas. Next, the group mapped the site of contact between IQGAP1 and ERK1/2 and demonstrated that a WW binding sequence was necessary for the interaction. A detached WW domain could block this interaction, and lentiviral delivery of WW peptide was able to inhibit the proliferation of MAPK-driven cell lines. This effect was restricted to cell lines with activated MAPK, and Ras-MAPK wild-type tumor cells were not responsive to this therapy. The authors also synthesized an IGGAP1 WW domain cell-penetrating fusion peptide, then demonstrated anticancer activity in cell culture and in vivo using this approach.

Whether these findings can be translated to the clinic remains to be seen, because peptide-based therapies have been more difficult to deliver than small molecules for the treatment of cancer patients. Nevertheless, maybe there is something to what Steve Jobs said about thinking differently.

K. L. Jameson et al., IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase–driven tumors. Nat. Med. 19, 626–630 (2013). [Full Text]

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