The receptor for insulin-like growth factor 1 (IGF-1) mediates multiple cellular responses, including stimulation of both proliferative and anti-apoptotic pathways. We have examined the role of cross talk between the IGF-1 receptor (IGF-1R) and the epidermal growth factor receptor (EGFR) in mediating responses to IGF-1. In COS-7 cells, IGF-1 stimulation causes tyrosine phosphorylation of the IGF-1R ␤ subunit, the EGFR, insulin receptor substrate-1 (IRS-1), and the Shc adapter protein. Shc immunoprecipitates performed after IGF-1 stimulation contain coprecipitated EGFR, suggesting that IGF-1R activation induces the assembly of EGFR⅐Shc complexes. Tyrphostin AG1478, an inhibitor of the EGFR kinase, markedly attenuates IGF-1-stimulated phosphorylation of EGFR, Shc, and ERK1/2 but has no effect on phosphorylation of IGF-1R, IRS-1, and protein kinase B (Akt). Cross talk between IGF-1 and EGF receptors is mediated through an autocrine mechanism involving matrix metalloprotease-dependent release of heparin-binding EGF (HB-EGF), because IGF-1-mediated ERK activation is inhibited both by [Glu 52 ]Diphtheria toxin, a specific inhibitor of HB-EGF, and the metalloprotease inhibitor 1,10-phenanthroline. These data demonstrate that IGF-1 stimulation of the IRS-1/PI3K/Akt pathway and the EGFR/Shc/ERK1/2 pathway occurs by distinct mechanisms and suggest that IGF-1-mediated "transactivation" of EGFR accounts for the majority of IGF-1-stimulated Shc phosphorylation and subsequent activation of the ERK cascade.The insulin receptor family is comprised of three members, the insulin receptor, the insulin-like growth factor-1 receptor (IGF-1R), 1 and the insulin receptor-related receptor, an orphan whose endogenous ligand is unknown. The three receptors share a common topology, each composed of two entirely extracellular ␣ subunits containing the ligand-binding domain, and two ␤ subunits that contain a single transmembrane domain and an intracellular domain possessing intrinsic ligand-stimulated tyrosine kinase activity. Like classical receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR), stimulation of insulin receptors leads both to receptor autophosphorylation and to the recruitment and activation of signaling proteins that contain specific phosphotyrosine-binding Src-homology 2 (SH2) domains.In the case of EGFR, phosphorylation of tyrosine residues within the intracellular domain provides docking sites for SH2 domain proteins, including the Ras guanine nucleotide exchange factor complex Grb2⅐mSos, Ras-GTPase-activating protein, phospholipase C␥, the p85⅐p110␣ phosphatidylinositol 3-kinase (PI3K) complex, and the nonreceptor tyrosine kinases c-Src and c-Fyn, as well as for adapter proteins such as Shc and Gab1. Thus the phosphorylated EGFR serves as a scaffold for the assembly, at the plasma membrane, of a multienzymesignaling complex that mediates the intracellular response to EGF (1). Unlike the EGF receptor, autophosphorylated insulin family receptors do not signal via the direct recruitment of these s...

Ipilimumab therapy resulted in clinically meaningful responses in advanced melanoma patients, and the results support further investigations of ipilimumab in combination with DTIC.

MDX-060 was well tolerated at doses up to 15 mg/kg. MDX-060 has limited activity as a single agent, but the minimal toxicity observed and the significant proportion of patients with stable disease suggests that further study of MDX-060 in combination with other therapies is warranted.