ALK ligand ALKAL2 potentiates MYCN-driven neuroblastoma in the absence of ALK mutation

High-risk neuroblastoma (NB) is responsible for a disproportionate number of childhood deaths due to cancer. One indicator of high-risk NB is amplification of the neural MYC (MYCN) oncogene, which is currently therapeutically intractable. Identification of anaplastic lymphoma kinase (ALK) as an NB oncogene raised the possibility of using ALK tyrosine kinase inhibitors (TKIs) in treatment of patients with activating ALK mutations. 8–10% of primary NB patients are ALK-positive, a figure that increases in the relapsed population. ALK is activated by the ALKAL2 ligand located on chromosome 2p, along with ALK and MYCN, in the “2p-gain” region associated with NB. Dysregulation of ALK ligand in NB has not been addressed, although one of the first oncogenes described was v-sis that shares > 90% homology with PDGF. Therefore, we tested whether ALKAL2 ligand could potentiate NB progression in the absence of ALK mutation. We show that ALKAL2 overexpression in mice drives ALK TKI-sensitive NB in t..... READ ARTICLE

EMBO DOI:10.15252/embj.2020105784

Authors: Marcus Borenäs, Ganesh Umapathy, Wei-Yun Lai, Dan E Lind, Barbara Witek, Jikui Guan, Patricia Mendoza-Garcia, Tafheem Masudi, Arne Claeys, Tzu-Po Chuang, Abeer El Wakil, Badrul Arefin, Susanne Fransson, Jan Koster, Mathias Johansson, Jennie Gaarder, Jimmy Van den Eynden, Bengt Hallberg and Ruth H Palmer

Chapter 4 - ALK Tyrosine Kinase Inhibitors in Drug Sensitization

Since the genomic aberrations of anaplastic lymphoma kinase (ALK) promote cancer cell proliferation and survival, specific tyrosine kinase inhibitors (TKIs) targeting these molecules have been developed. Besides its original targeting ALK effect, several studies have reported that ALK inhibitors can modulate the ATP-binding cassette (ABC) transporter to reverse the multiple drug resistance (MDR), which is one of the major obstacles for the successful cancer chemotherapy. In this chapter, we highlight reports manifesting that ALK inhibitors, including crizotinib, ceritinib, alectinib, and lorlatinib to antagonize ABC transporters to re-sensitize the anticancer drug in vitro and in vivo. These results give us some hints that specific ALK TKIs in combination with conventional anticancer drugs may be a good strategy to overcome the MDR in the clinic. READ ARTICLE

Protein Kinase Inhibitors as Sensitizing Agents for Chemotherapy DOI:10.1016/B978-0-12-816435-8.00004-3

Authors: Tong Wu, Liwu Fu

Treating ALK-positive non-small cell lung cancer

Targeting genomic alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements, have radically changed the treatment of patients with non-small cell lung cancer (NSCLC). In the case of ALK-rearranged gene, subsequent rapid development of effective genotype-directed therapies with ALK tyrosine kinase inhibitors (TKIs) triggered major advances in the personalized molecularly based approach of NSCLC. Crizotinib was the first-in-class ALK TKI with proven superiority over standard platinum-based chemotherapy for the 1st-line therapy of ALK-rearranged NSCLC patients. However, the acquired resistance to crizotinib and its diminished efficacy to the central nervous system (CNS) relapse led to the development of several novel ALK inhibitors, more potent and with different selectivity compared to crizotinib. To date, four ALK TKIs, crizotinib, ceritinib, alectinib and brigatinib have received approval from the Food and Drug Admin..... READ ARTICLE

Annals of Translational Medicine DOI:10.21037/atm.2017.11.34

Authors: Dimitrios C. Ziogas,corresponding author Anna Tsiara, Georgios Tsironis, Maria Lykka, Michalis Liontos, Aristotelis Bamias, and Meletios-Athanasios Dimopoulos