Highlights of This Issue Free

Despite a well-documented role of insulin-like growth factor I receptor (IGF-IR) in experimental tumor models, IGF-IR antibodies failed to demonstrate compelling clinical activity in unselected populations of cancer patients. Forest and colleagues demonstrate that the antitumor activity of the IGF-IR antibody (cixutumumab) can be compromised by expression of insulin receptor isoforms A and B and further show that IGF-II is a key mediator of primary tumor resistance to the antibody in this setting. This study therefore provides a rationale for more personalized clinical trials enriched for cancer patients whose tumors display low IR expression.

Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer death in both men and women. Sulfiredoxin (Srx) is a reductase that restores the peroxidase activity of over-oxidized peroxiredoxins. Using loss-of-function, gain-of-function experiments and orthotopical mouse model of CRC development, a critical role of Srx to drive CRC cell invasion and metastasis is revealed. Mechanistically, Srx enhances the activation of EGFR signaling through the inhibition of receptor acetylation at K1037. This study indicates that Srx can be used as a molecular target to develop novel chemotherapeutics for CRC treatment.

Glucocorticoids are commonly used to treat B acute lymphoblastic leukemia (B-ALL), but its mechanism of action remains enigmatic. Here, Consolaro and colleagues determine that in response to dexamethasone, FOXO3a translocates into the nucleus and elicits the expression of downstream targets important for proliferative arrest and cell death. FOXO3a activation by dexamethasone is mediated through its Ser-7 phosphorylation and Lys-242/5 acetylation. These findings expose FOXO3a and its post-translational modifications as essential for dexamethasone response, which can be exploited for B-ALL diagnosis and treatment.

Prostate cancer (PCa) requires AR signaling throughout all disease stages, while Myc deregulation often occurs and correlates with aggressiveness. Recently, a sphingosine kinase-2 inhibitor (ABC294640) was reported to deplete Myc expression. In the current study, Schrecengost and colleagues investigate the impact of ABC294640 on early stage and therapy-resistant PCa, and found concurrent Myc and AR gene and protein downregulation. This corresponded with cellular growth inhibition and suppression of tumor growth in vivo. Given the need for durable treatments that block AR signaling, these results represent a novel therapeutic approach that targets two prominent oncogene axes.