The Insulin Receptor Substrate (IRS) proteins are cytoplasmic adaptor proteins that function as essential signaling intermediates downstream of activated cell surface receptors, many of which have been implicated in cancer. The IRS proteins do not contain any intrinsic kinase activity, but rather serve as scaffolds to organize signaling complexes and initiate intracellular signaling pathways. As common intermediates of multiple receptors that can influence tumor progression, the IRS proteins are positioned to play a pivotal role in regulating the response of tumor cells to many different microenvironmental stimuli. Limited studies on IRS expression in human tumors and studies on IRS function in human tumor cell lines and in mouse models have provided clues to the potential function of these adaptor proteins in human cancer. A general theme arises from these studies; IRS-1 and IRS-4 are most often associated with tumor growth and proliferation and IRS-2 is most often associated with tumor motility and invasion. In this review, we discuss the mechanisms by which IRS expression and function are regulated and how the IRS proteins contribute to tumor initiation and progression.

The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor molecules that function as signaling intermediates downstream of activated cell surface receptors. Based on data implicating IRS-2 but not IRS-1 in breast cancer invasion, survival, and metastasis, we assessed the contribution of IRS-1 and IRS-2 to aerobic glycolysis, which is known to impact tumor growth and progression. For this purpose, we used tumor cell lines derived from transgenic mice that express the polyoma virus middle T antigen (PyV-MT) in the mammary gland and that are wild-type (WT) or null for either Irs-1 (Irs-1 ؊/؊ ) or Irs-2 (Irs-2 ؊/؊ ). Aerobic glycolysis, as assessed by the rate of lactic acid production and glucose consumption, was diminished significantly in Irs-2 ؊/؊ cells when compared with WT and Irs-1 ؊/؊ cells. Expression of exogenous Irs-2 in Irs-2 ؊/؊ cells restored the rate of glycolysis to that observed in WT cells. The transcription factor FoxO1 does not appear to be involved in Irs-2-mediated glycolysis. However, Irs-2 does regulate the surface expression of glucose transporter 1 (Glut1) as assessed by flow cytometry using a Glut1-specific ligand. Suppression of Glut1 expression inhibits Irs-2-dependent invasion, which links glycolysis to mammary tumor progression. Irs-2 was shown to be important for mammalian target of rapamycin (mTor) activation, and Irs-2-dependent regulation of Glut1 surface expression is rapamycin-sensitive. Collectively, our data indicate that Irs-2, but not Irs-1, promotes invasion by sustaining the aerobic glycolysis of mouse mammary tumor cells and that it does so by regulating the mTor-dependent surface expression of Glut1.Glucose metabolism in cancer cells differs significantly from that of normal cells as observed initially by Warburg in the 1920s (1). Specifically, cancer cells depend more on glycolysis than oxidative phosphorylation to generate ATP, even in high oxygen tensions. Subsequent studies have affirmed the importance of aerobic glycolysis in tumor progression and have shown that it provides tumor cells with a selective advantage in their ability to progress toward invasive and metastatic disease (2-4). Significantly, the "Warburg effect" has become a powerful and standard imaging technique for detecting tumors and their metastases by positron emission tomography using [ 18 F]deoxyglucose (5). Aerobic glycolysis is also an ideal target for therapeutic intervention because apoptosis results if this process is perturbed (2, 6). To exploit aerobic glycolysis for the clinical management of cancer, however, much more needs to be learned about how this form of metabolism is induced and sustained in tumors. Our interest is in understanding how aerobic glycolysis is regulated in breast cancer.The insulin receptor substrate (IRS) 3 proteins are cytoplasmic adaptor molecules that function as signaling intermediates downstream of activated cell surface receptors (7). The role of the IRS-2 family member is of particular significance in breast cancer. IRS-2 is predominantly expressed ...

The receptor tyrosine kinase KIT is an established oncogenic driver of tumor growth in certain tumor types, including gastrointestinal stromal tumors, in which constitutively active mutant forms of KIT represent an actionable target for small-molecule tyrosine kinase inhibitors. There is also considerable potential for KIT to influence tumor growth indirectly based on its expression and function in cell types of the innate immune system, most notably mast cells. We have evaluated syngeneic mouse tumor models for antitumor effects of an inhibitory KIT mAb, dosed either alone or in combination with immune checkpoint inhibitors. Anti-KIT mAb treatment enhanced the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs, and promoted immune responses by selectively reducing the immunosuppressive monocytic myeloid-derived suppressor cell population and by restoring CD8 and CD4 T-cell populations to levels observed in naïve mice. These data provide a rationale for clinical investigation of the human KIT-specific mAb KTN0158 in novel immuno-oncology combinations with immune checkpoint inhibitors and other immunotherapeutic agents across a range of tumor types. .

<p>Supplemental Figure S1A - Gating Plot Example for Identification of MDSC Populations in Spleen Samples (Pan02 Study); Supplemental Figure S1B - Gating Plot Example for Identification of T-Cell Populations in Tumor Samples (Pan02 Study); Supplemental Figure S2 - Inhibition of Mammalian KIT by KTN0158; Supplemental Figure S3 - Growth of Colon26 Tumor Cells In Vitro is SCF/KIT-Signaling Independent; Supplemental Figure S4 - Individual Tumor Growth Curves from the Colon26 Efficacy Study.</p>

<p>Supplemental Figure S1A - Gating Plot Example for Identification of MDSC Populations in Spleen Samples (Pan02 Study); Supplemental Figure S1B - Gating Plot Example for Identification of T-Cell Populations in Tumor Samples (Pan02 Study); Supplemental Figure S2 - Inhibition of Mammalian KIT by KTN0158; Supplemental Figure S3 - Growth of Colon26 Tumor Cells In Vitro is SCF/KIT-Signaling Independent; Supplemental Figure S4 - Individual Tumor Growth Curves from the Colon26 Efficacy Study.</p>