Background: Insulin-like growth factor (IGF) II interacts with IR-A and is a more powerful mitogen than insulin. Results: IGF-II and insulin differ in regulating insulin receptor (IR)-A trafficking and stability. Conclusion: Compared with insulin, IGF-II induces lower IR-A and downstream effectors activation but protects IR-A and IRS-1 from down-regulation, thereby evoking a sustained mitogenic stimulus. Significance: These results further elucidate the mechanisms controlling IR-A biological responses.
The isoform A of the insulin receptor (IR) (IR-A) is a bifunctional receptor, because it binds both insulin and IGF-II. IR-A activation by IGF-II plays a role in development, but its physiological role in adults is unknown. IGF-II signaling through IR-A is deregulated in cancer and favors tumor progression. We hypothesized that IGF-II binding to the IR-A elicits a unique signaling pathway. In order to obtain an unbiased evaluation of IR-A substrates differentially involved after IGF-II and insulin stimulation, we performed quantitative proteomics of IR-A substrates recruited to tyrosine-phosphorylated protein complexes using stable isotope labeling with amino acids in cell culture in combination with antiphosphotyrosine antibody pull down and mass spectrometry. Using cells expressing only the human IR-A and lacking the IGF-I receptor, we identified 38 IR-A substrates. Only 10 were known IR mediators, whereas 28 substrates were not previously related to IR signaling. Eleven substrates were recruited by stimulation with both ligands: two equally recruited by IGF-II and insulin, three more strongly recruited by IGF-II, and six more strongly recruited by insulin. Moreover, 14 substrates were recruited solely by IGF-II and 13 solely by insulin stimulation. Interestingly, discoidin domain receptors, involved in cell migration and tumor metastasis, and ephrin receptor B4, involved in bidirectional signaling upon cell-cell contact, were predominantly activated by IGF-II. These findings indicate that IR-A activation by IGF-II elicits a unique signaling pathway that may play a distinct role in physiology and in disease.
Venetoclax, an orally bioavailable inhibitor of BCL-2, was approved in 2016 by the United States Food and Drug Administration (FDA) for the treatment of chronic lymphocytic leukemia (CLL) patients with 17p deletion [del(17p)], who have received at least one prior therapy. Areas covered: We focus on the mechanism of action of venetoclax and on the clinical trial data that led to the approval of venetoclax for CLL patients. We also review the studies in which this drug has being explored in combination with other anti-CLL drugs. Expert opinion: Data from early clinical trials have shown that venetoclax, as a single agent, is highly effective for relapsed/refractory CLL patients, including those cases with high-risk features. Furthermore, venetoclax seems to be an appropriate option for patients who progress on B-cell receptor (BCR) pathway kinase inhibitors. Venetoclax is also safe, with the most common serious adverse events being neutropenia. The risk of tumor lysis syndrome (TLS) can be reduced by a slow dose ramp-up, careful monitoring, and adequate prophylaxis. Ongoing trials will further clarify the safety and efficacy of venetoclax in combination with other drugs in both relapsed/refractory and untreated CLL patients.
Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.
Bendamustine seems to be efficacious either in monotherapy or in combination with other drugs in previously treated or untreated patients. This is due to its unique mechanism of action including its ability to activate apoptosis and inhibit mitotic checkpoints, making it potentially more effective than other alkylating agents. Moreover, it has an acceptable toxicity profile and is suitable for patients with renal impairment. Finally, this drug does not seem to compromise the possibility of achieving a stem-cell mobilization. Nonetheless, data from Phase III studies demonstrating its effectiveness in terms of overall survival are not yet available.
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