Therapeutic Targeting of the Anaplastic Lymphoma Kinase (ALK) in Neuroblastoma—A Comprehensive Update

Neuroblastoma (NBL) is an embryonic malignancy of the sympathetic nervous system and mostly affects children under the age of five. NBL is highly heterogeneous and ranges from spontaneously regressing to highly aggressive disease. One of the risk factors for poor prognosis are aberrations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK), which is involved in the normal development and function of the nervous system. ALK mutations lead to constitutive activation of ALK and its downstream signalling pathways, thus driving tumorigenesis. A wide range of steric ALK inhibitors has been synthesized, and several of these inhibitors are already in clinical use. Major challenges are acquired drug resistance to steric inhibitors and pathway evasion strategies of cancer cells upon targeted therapy. This review will give a comprehensive overview on ALK inhibitors in clinical use in high-risk NBL and on the potential and limitations of novel inhibitors. Because combinatory treatment..... READ ARTICLE

Pharmaceutics DOI:10.3390/pharmaceutics13091427

Authors: Annette K. Brenner and Maria W. Gunnes

$Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)$

Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)

Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The ..... READ ARTICLE

Clinical Cancer Research DOI:10.1158/1078-0432.CCR-20-4224

Authors: Jennifer H. Foster, Stephan D. Voss, David C. Hall, Charles G. Minard, Frank M. Balis, Keith Wilner, Stacey L. Berg, Elizabeth Fox, Peter C. Adamson, Susan M. Blaney, Brenda J. Weigel and Yael P. Mossé

Case Study, group4Kirk SmithJuly 1, 2021ALK, neuroblastoma, pediatric, crizotinib

Exceptional response to the ALK and ROS1 inhibitor lorlatinib and subsequent mechanism of resistance in relapsed ALK F1174L-mutated neuroblastoma

In summary, we describe a patient with relapsed, refractory neuroblastoma harboring the ALK F1174L mutation resistant to the first-generation ALK inhibitor crizotinib combined with chemotherapy in whom lorlatinib induced a durable complete remission of 13 mo. However, as is often the case with targeted therapeutic approaches, resistance, potentially mediated by new genomic alterations including CDK4 and FGFR1 amplification and NRAS mutation, led to disease recurrence. Our case provides an example of clinical benefit made possible by the development of next-generation ALK inhibitors but also highlights the need for increased understanding of mechanisms of acquired resistance. We propose that molecular monitoring during therapy may guide rational combination multidrug approaches to overcome and prevent resistance. READ ARTICLE

Cold Spring Harbor: Molecular Case Studies DOI:10.1101/mcs.a006064

Authors: Tingting Liu, Matthew D., Merguerian, Steven P. Rowe, Christine A. Pratilas, Allen R. Chen and Brian H. Ladle

Case Study, group4Kirk SmithJuly 1, 2021neuroblastoma, pediatric, ALK, lorlatinib, crizotinib combination

E273 Extracellular domain shedding of the ALK receptor mediates neuroblastoma cell migration Screen reader support enabled.

Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ~10%
of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most
non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage.
Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT ALK significantly impedes NB cell migration with subsequent prolongation of survival in mouse models. Cleavage inhibition results in the downregulation of an epithelial-to-mesenchymal transition (EMT) gene signature, with decreased nuclear localization and occupancy of b-catenin at EMT gene promoters. We further show that
cleavage is mediated by matrix metalloproteinase 9, whose genetic and pharmacologic inactivation inhibits
cleavage and decreases NB cell migration. Together, our results indicate a pivotal role for WT ALK ECD cleavage in NB pathogenesis, which may be harnessed for therapeutic benefit. READ ARTICLE

Cell Reports DOI:10.1016/J.CELREP.2021.109363

Authors: Hao Huang, Alexander Gont, Lynn Kee, Ruben Dries, Kathrin Pfeifer, Bandana Sharma, David N. Debruyne, Matthew Harlow, Satyaki Sengupta, Jikui Guan, Caleb M. Yeung, Wenchao Wang, Bengt Hallberg, Ruth H. Palmer, Meredith S. Irwin, Rani E. George

Therapeutic Strategies to Overcome ALK Resistance in Cancer

Therapeutic Strategies to Overcome ALK Resistance in Cancer, Volume 13, presents current strategies to improve and prolong clinical benefit in ALK driven cancers. Most patients with ALK-driven cancer are sensitive to tyrosine kinase inhibitor (TKI) therapy, but resistance invariably develops. This book discusses topics such as structure and function of ALK, ALK rearranged lung cancer, resistance mechanisms to ALK TKI tumors, and novel therapeutic strategies to enhance crizotinib anti-tumor efficacy in ALCL. Additionally, it encompasses information on drug combinations to enhance ALK TKI anti-tumor efficacy in neuroblastoma and future perspectives in the field. This book is a valuable resource for cancer researchers, clinicians and several members of biomedical field who need to understand more about how to fight ALK resistance in cancer treatment. READ ARTICLE

Academic Press DOI: 10.1016/C2019-0-03295-5

Edited by: Luc Friboulet

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

Neuroblastoma is a childhood disease that has 8-10% ALK positive and may be higher in the replapse population. Overexpression of ALKAL2 (ligand for ALK) located on chromosome 2p with neutral MYC oncogene can drive neuroblastoma in the absense of ALK mutation. READ ARTICLE

European Molecular Biology Organization (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, Ruth H Palmer

Clinical TrialsKirk SmithJanuary 1, 2021ALK receptor, neuroblastoma, neural MYC, MYCN, oncogene, ALKAL2 ligand