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Anaplastic lymphoma kinase (ALK) is a receptor-type tyrosine kinase. Human normal ALK is a single-stranded transmembrane protein containing 1,620 amino acids. Under normal circumstances, ALK is only expressed in the nervous system, and its expression level decreases with the development of brain development, and the content of mature brain tissue is low.
ALK and Non-Small Cell Lung Cancer (NSCLC)
Solomon et al. showed that fusion of EML4-ALK leads to aberrant expression of ALK and activation of ALK tyrosine kinase and downstream signaling pathways. The end result is uncontrolled proliferation and survival of cancer cells.
Figure 1. ALK activation and downstream signaling in ALK-rearranged NSCLC. (Solomon, B., et al, 2014)
Non-small cell lung cancer (NSCLC) is one of the most serious diseases in human life, with ALK positive patients accounting for 3% to 5%. In recent years, numerous small molecule ALK inhibitors have been developed for the treatment of ALK positive NSCLC. Compared with traditional chemotherapeutic drugs, the first-generation ALK inhibitor crizotinib has a significant effect on ALK-positive NSCLC patients and has become the first-line treatment for ALK-positive NSCLC therapy, but the emergence of drug resistance limits its clinical application. A new generation of ALK inhibitors, ceritinib and erlotinib, have also been approved by the FDA. More new ALK inhibitors with better safety, higher selectivity or better activity are under development. These drugs are expected to overcome the resistance of crizotinib and other marketed drugs, giving more options to patients with ALK-positive NSCLC.
The echinoderm microtubule-associated protein-like 4-mutated lymphoma kinase (EML4-ALK) fusion gene found in NSCLC is another major advance in targeted therapy for lung cancer. In particular, it was subsequently confirmed that crizotinib has a definite therapeutic effect on ALK-positive NSCLC, and it has brought hope to treatment in a specific population. A study reported by Shaw et al. showed that 80 patients with ALK-positive NSCLC who had been treated with crizotinib had an overall response rate of 85%, and crizotinib was effective regardless of the presence or absence of ALK-resistant mutations.
ALK Abnormalities and Neuroblastoma
Neuroblastoma (NB) is the most common malignant extracranial solid tumor in childhood. ALK activates mutations in more than 20 forms. ALK function-acquired mutations have been reported in both familial and sporadic NB. Studies have shown that activating mutations in ALK proteins are the major carcinogenic mechanisms of most hereditary NB, with a prevalence of 12.4% in high-risk cases and 3% to 11% in sporadic children. Studies have found that ALK mutations occur in highly conserved domains of tyrosine kinases and lead to increased kinase activity, with the two most common mutation hotspots being F1174 and R1275. The occurrence of ALK is mostly associated with clinical progression or MYCN gene amplification, and it is speculated that ALK mutations may indicate a poor clinical outcome of NB.
Schleiermacher et al. found a new ALK mutation in a subcloned sample of NB recurrence, emphasizing that deep sequencing and continuous sampling detection of ALK are important for therapeutic decision making. The MYCN gene is located on the human chromosome 2p24, adjacent to the ALK site. Hasan et al. believe that ALK is a direct transcriptional target for MYCN. ALK amplification may be closely related to the malignant biological behavior and poor prognosis of NB.
ALK Abnormalities and Rhabdomyosarcoma
Rhabdomyosarcoma (RMS) is the most common malignant soft tissue sarcoma in childhood and adolescence, accounting for 3% to 7% of childhood malignancies. About 350 new cases are diagnosed each year in the United States. According to the type of histology, it is mainly divided into two subtypes: embryonic rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS).
There is also an increase in ALK gene amplification, mutation, and protein expression in RMS. It indicates that the positive rate of ALK protein in ARMS is higher than ERMS, the former is 50% to 92%, and the latter is only 15% to 39%. Bonvini et al. reported that high expression of ALK transcripts is associated with the malignant biological behavior of tumors, high tumor burden, and high tumor stage. The frequency of amplification of ALK in ARMS is 6% to 17%. The ALK inhibitor NVP-TAE684 reduces the viability of RMS, especially the ARMS cell line. Studies have shown that two of the six cell lines with ALK overexpression are sensitive to ALK inhibitors.
ALK Abnormality and Anaplastic Large Cell Lymphoma
Anaplastic large cell lym⁃phoma (ALCL) belongs to peripheral T-cell lymphoma, accounting for 10% to 15% of non-Hodgkin's lymphoma in children and adolescents. ALCL is the most common type of T-cell non-Hodgkin's lymphoma in children. The positive rate of ALK gene rearrangement in ALCL is 65%-85%, mainly in children and adolescents, mainly male. The most common karyotype abnormality of ALK-positive ALCL is t(2;5)(p23;q35) translocation, accounting for 70%-80%. This ectopic results in the formation of NPM-ALK fusion proteins, ALK protein overexpression, and constitutive tyrosine kinase activation. Genes involved in translocation also include TPM3, TPM4, TFG, MSN, CLTC, and ATIC. Therefore, in addition to the treatment of ALK expression and enzyme activity, key effector molecules in the ALK fusion gene-mediated signaling pathway are also important therapeutic targets. In vitro experiments showed that crizotinib has good anti-tumor activity in the treatment of NPM-ALK-positive ALCL by inducing apoptosis and down-regulating oncoproteins.
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