1.Activating mutations in ALK kinase domain confer resistance to structurally unrelated ALK inhibitors in NPM-ALK-positive anaplastic large-cell lymphoma.
Zdzalik D1, Dymek B, Grygielewicz P, Gunerka P, Bujak A, Lamparska-Przybysz M, Wieczorek M, Dzwonek K. J Cancer Res Clin Oncol. 2014 Apr;140(4):589-98. doi: 10.1007/s00432-014-1589-3. Epub 2014 Feb 8.
PURPOSE: Crizotinib, the first FDA-approved ALK inhibitor, showed significant antitumor activity in young patients with anaplastic large-cell lymphoma (ALCL) frequently displaying ALK rearrangement. However, long-term therapeutic benefits of crizotinib are limited due to development of drug resistance. CH5424802--more potent and selective ALK inhibitor--comprises a good candidate for second-line treatment in crizotinib-relapsed patients. The aim of this study was to determine possible mechanisms of resistance to ALK inhibitors that can appear in ALCL patients.
2.Blocking the PI3K pathway enhances the efficacy of ALK-targeted therapy in EML4-ALK-positive nonsmall-cell lung cancer.
Yang L1, Li G, Zhao L, Pan F, Qiang J, Han S. Tumour Biol. 2014 Oct;35(10):9759-67. doi: 10.1007/s13277-014-2252-y. Epub 2014 Jun 29.
Targeted therapy based on ALK tyrosine kinase inhibitors (ALK-TKIs) has made significant achievements in individuals with EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion positive nonsmall-cell lung cancer (NSCLC). However, a high fraction of patients receive inferior clinical response to such treatment in the initial therapy, and the exact mechanisms underlying this process need to be further investigated. In this study, we revealed a persistently activated PI3K/AKT signaling that mediates the drug ineffectiveness. We found that genetic or pharmacological inhibition of ALK markedly abrogated phosphorylated STAT3 and ERK, but it failed to suppress AKT activity or induce apoptosis, in EML4-ALK-positive H2228 cells. Furthermore, targeted RNA interference of PI3K pathway components restored sensitivity to TAE684 treatment at least partially due to increased apoptosis. Combined TAE684 with PI3K inhibitor synergistically inhibited the proliferation of EML4-ALK-positive cells in vitro and significantly suppressed the growth of H2228 xenografts in vivo, suggesting the potential clinical application of such combinatorial therapy regimens in patients with EML4-ALK positive lung cancer.
3.Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance.
Chen Z1, Akbay E, Mikse O, Tupper T, Cheng K, Wang Y, Tan X, Altabef A, Woo SA, Chen L, Reibel JB, Janne PA, Sharpless NE, Engelman JA, Shapiro GI, Kung AL, Wong KK. Clin Cancer Res. 2014 Mar 1;20(5):1204-11. doi: 10.1158/1078-0432.CCR-13-1733. Epub 2013 Dec 10.
PURPOSE: To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion.
4.Mutation-Independent Activation of the Anaplastic Lymphoma Kinase in Neuroblastoma.
Regairaz M1, Munier F2, Sartelet H3, Castaing M4, Marty V5, Renauleaud C2, Doux C2, Delbé J6, Courty J6, Fabre M7, Ohta S8, Viehl P9, Michiels S4, Valteau-Couanet D10, Vassal G11. Am J Pathol. 2016 Feb;186(2):435-45. doi: 10.1016/j.ajpath.2015.10.016. Epub 2015 Dec 12.
Activating mutations of anaplastic lymphoma kinase (ALK) have been identified as important players in neuroblastoma development. Our goal was to evaluate the significance of overall ALK activation in neuroblastoma. Expression of phosphorylated ALK, ALK, and its putative ligands, pleiotrophin and midkine, was screened in 289 neuroblastomas and 56 paired normal tissues. ALK was expressed in 99% of tumors and phosphorylated in 48% of cases. Pleiotrophin and midkine were expressed in 58% and 79% of tumors, respectively. ALK activation was significantly higher in tumors than in paired normal tissues, together with ALK and midkine expression. ALK activation was largely independent of mutations and correlated with midkine expression in tumors. ALK activation in tumors was associated with favorable features, including a younger age at diagnosis, hyperdiploidy, and detection by mass screening. Antitumor activity of the ALK inhibitor TAE684 was evaluated in wild-type or mutated ALK neuroblastoma cell lines and xenografts.
