Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome–Positive Acute Lymphoblastic LeukemiaReport as inadecuate




Small Molecule ErbB Inhibitors Decrease Proliferative Signaling and Promote Apoptosis in Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia - Download this document for free, or read online. Document in PDF available to download.

The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia Ph+ALL is a negative prognostic indicator. Tyrosine kinase inhibitors TKI that target BCR-ABL, such as imatinib, have improved treatment of Ph+ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 ErbB2 is expressed in ∼30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array RPPA with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph+ALL as compared to just 4.8% of Ph−ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 by 60% in Z119 and 39% in Z181 cells at 3 µM. Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner by 91% in both cell lines at 3 µM. Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1-2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR-ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph+ALL and encourage the development of clinical strategies combining ErbB and BCR-ABL kinase inhibitors for this subset of ALL patients.



Author: Mary E. Irwin, Laura D. Nelson, Janice M. Santiago-O’Farrill, Phillip D. Knouse, Claudia P. Miller, Shana L. Palla, Doris R. Si

Source: http://plos.srce.hr/



DOWNLOAD PDF




Related documents