The function and importance of ALK TRK in development and disease

Research project
Active research
Project owner
Institute of Biomedicine

Short description

Bengt Hallberg's research group aims at understanding signaling downstream of the onco-driver ALK and other ALK-fusion proteins. Such knowledge is necessary fort the nuances of the various ALK proteins to be better understood from a biological point of view and for future clinical treatment so that patients are treated accordingly.

Our aim 

Our aim is to reveal pathways, mechanisms and downstream targets of ALK mediated signaling in ALK positive Non-Small-Cell-Lung-Cancer (NSCLC) and in pediatric neuroblastoma. Further, a goal is to understand drug resistance mechanisms and changes in the genomic set up of resistant NSCLC and neuroblastoma cells. Such information will improve our understanding of ALK from a mechanistic point of view. For sure such information will also improve selection of possible combination treatment that are optimal for specific NSCLC and neuroblastoma patients. We hope to examine the effect of current ALK targeting drugs either alone or in combination with novel downstream targets of ALK.     

Short background about ALK 

ALK was first discovered in 1994 as a fusion protein in a cell line generated from a patient with anaplastic large cell lymphoma. Subsequent cloning revealed the identity of this chimeric protein as a fusion between NPM (nucleophosmin) and the intracellular kinase domain of a novel receptor tyrosine kinase (RTK) and three years later the cloning of full-length ALK was reported. The ALK locus encodes for a classical RTK containing an extracellular ligand-binding domain, a transmembrane domain and an intracellular tyrosine kinase domain.  The expression pattern of ALK in chicken, mice, rats and humans suggests key roles in development of the nervous system and functional physiological roles have been observed in several model systems, such as Drosophila, C. elegans, and zebra fish. Last year we also reported that ALKAL1 and ALKAL2 (FAM150A and FAM150B) are potent ligand activators of ALK, finally de-orphanising ALK and thereby solving a long standing enigma.   

Non-Small-Cell Lung Cancer (NSCLC) 

Lung cancer can clinically be divided into two major subgroups: small-cell-lung-cancer (SCLC) and non-small-cell-lung-cancer (NSCLC), with type being critical for patient’s treatment. NSCLC accounts for approximately 80 percent of all lung cancers and include subtypes such as squamous cell lung carcinoma, large-cell lung carcinoma, and adenocarcinoma, all of which respond poorly to conventional cancer treatments.    

Both the National Cancer Institute’s Lung Cancer Mutations Consortium and a French lung cancer consortium have reported results from >1000 of patient samples in an attempt to catalogue driver mutations and translocations in NSCLC. Their results suggest that NSCLC should be regarded as a number of molecularly different diseases, with 60 percent of tumours exhibiting driver mutations. These include KRAS (22 percent) and EGFR (17 percent) and others such as BRAF, HER2 and EML4-ALK (7 percent), and therefore should they be treated accordingly.       

ALK mutations in NSCLC patients 

ALK first entered the field of NSCLC in 2007, when two groups employing very different experimental approaches simultaneously reported the presence of ALK fusion proteins in lung tumours. Today ALK translocation products is now recognized as an increasing population of lung cancer patients with adenocarcinoma histology, younger and non-smokers.  Initial reports of the promising therapeutic potential of ALK TKIs for the treatment of ALK-positive patients with NSCLC was accompanied by reports of relapse, typically within a year, and identification of crizotinib-induced secondary mutations, so called resistance mutations that interfere with crizotinib binding through steric hindrance and allow continued ALK activation in the presence of crizotinib. Ultimately, this results in renewed tumor growth. Today more than 11 different resistance mutations have been observed in ALK that confer resistance against different FDA approved ALK drugs, resulting in serious complications in the treatment of ALK-positive NSCLC patients. Our aim is to investigate mechanisms and aid in identification of drug/drug combinations that offer better therapeutic potential in the different ALK positive cancers compare to today treatment but also to track the secondary mutations faster.    


Neuroblastoma, a tumor of the developing nervous system accounts for 15 percent of all pediatric oncology death. Neuroblastoma is a heterogeneous disease and while a subset may undergo spontaneous differentiation or regression with little or no therapy, the majority are difficult to cure with current regimes. The most common genetic features of neuroblastoma are amplification of the proto-oncogene MYCN, deletions of parts of chromosome arms 1p and 11q, gain of parts of 17q and triploidy.    

ALK mutations in neuroblastoma 

In both familial and sporadic neuroblastoma, which is a childhood cancer arising from the sympathetic nervous system, full length ALK is activated by point mutations, predominantly in the kinase domain. While activating neuroblastoma mutations are spread throughout the kinase domain; the majority are located in one of three hotspot residues: Phe1174, Arg1275 and Phe1245, and are observed at increased frequencies in relapsed patients.  malignancies in both pediatric and adult patient populations. Neuroblastoma is a heterogeneous tumor that exhibits numeric gains and losses of chromosome regions which may contribute to the complexity of the disease. We will increase our understanding of ALK signaling in neuroblastoma, neuroblastoma mutants fall into three classes: gain-of-function (GOF) ligand-independent mutations, ligand-dependent mutations which are not constitutively active and require activation with either ALKAL1 and ALKAL2 or agonist antibodies, and finally kinase-dead mutations. The ability of ALKAL ligands to further activate mutant ALK  suggests that dysregulation of the ALKAL ligands may potentially play a role in neuroblastoma. ALK is an attractive and targetable therapeutic target in neuroblastoma. Various small-molecule ALK tyrosine kinase inhibitors (TKIs) show clinical activity against ALK. 

Group members

Dan Emil Lind

Tzu-Po Chuang

Wei-Yun Lai

Edit Zenténius

Joachim Siaw

Wasi Alam