Disruption of IQGAP1 scaffold function inhibits oncogenic ERK signaling without toxicity.
Major finding: Disruption of IQGAP1 scaffold function inhibits oncogenic ERK signaling without toxicity.
Clinical relevance: An IQGAP1 peptide reduces RAS/RAF–driven tumor growth and bypasses vemurafenib resistance.
Impact: Blockade of scaffold-kinase interactions can complement direct kinase inhibition.
The clinical effectiveness of mitogen-activated protein kinase (MAPK) pathway kinase inhibitors is often limited by acquired resistance and by toxicities caused by inhibition of essential kinases in normal cells. Jameson and colleagues hypothesized that disruption of IQ motif–containing GTPase activating protein 1 (IQGAP1), an intracellular scaffold protein that binds and facilitates interactions among RAF, MAP–ERK kinase (MEK), and ERK, might represent an alternative approach to suppress MAPK signaling and may circumvent resistance mechanisms associated with direct kinase inhibition. Furthermore, because Iqgap1-null mice are viable and fertile, IQGAP1 may likely be safely targetable in human cells. Consistent with a role for IQGAP1 in tumorigenesis, Iqgap1 was required for Hras-driven tumor formation in mice. IQGAP1 depletion also suppressed basement membrane degradation and invasion in RAS-transformed human epidermal tissue but did not cause the hypoplastic tissue collapse seen with ERK inhibition, likely because depletion of IQGAP1 did not completely eliminate ERK kinase activity. Blockade of the IQGAP1–ERK interaction through lentiviral expression of the IQGAP1 WW domain required for ERK binding or use of a cell-permeable IQGAP1 WW peptide blocked IQGAP1 from binding to ERK, suppressed ERK activation, and specifically impaired proliferation and invasion in cancer cell lines with MAPK activation caused by KRAS or BRAF mutation. IQGAP1 blockade also inhibited growth of established MAPK pathway–mutant tumors, and systemic WW peptide delivery significantly slowed progression of murine tumor models without detectable morbidity. Importantly, BRAF-mutant melanoma cell lines with acquired resistance to the kinase inhibitor vemurafenib retained sensitivity to the IQGAP1 WW peptide, providing further evidence that scaffold and direct kinase inhibition are non-redundant. Together, these findings support clinical development of inhibitors of IQGAP1 scaffold activity and provide proof-of-principle that targeting scaffold–kinase interactions can complement existing approaches to inhibit oncogenic kinase signaling.
Jameson KL, Mazur PK, Zehnder AM, Zhang J, Zarnegar B, Sage J, et al. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase–driven tumors. Nat Med 2013;19:626–30.
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