BY MARCIO ALVAREZ-SILVA

The ALK was discovered in 1994 as a fusion in t(2;5) chromosomal translocation in large-cell anaplastic lymphoma (ALCL), which occurs in most non-Hodgkin's anaplastic cell lymphomas, of which the ALK was named [1]. This study demonstrated the fusion of the nucleolar nucleophosmin (NPM) gene, on chromosome 5q35, with a tyrosine kinase protein ALK gene, on chromosome 2p23. The ALK encodes a tyrosine kinase receptor, and its expression in humans is limited to the nervous system, testicles, small intestine, and dispersed pericytes. Its level of expression is unusually high in the neonatal phase, implying an essential role in development [2].

​

The fusion proteins with ALK, which the kinase domain of ALK is fused to the amino-terminal portion of several proteins, have been described in numerous cancers: anaplastic large cell lymphoma, inflammatory myofibroblastic tumor, diffuse large B-cell lymphoma, non-small-cell lung cancer (NSCLC), renal medullary carcinoma, renal cell carcinoma, breast cancer, colon carcinoma, serous ovarian carcinoma, and esophageal squamous cell carcinoma. Mutations in ALK described in NSCLC, inflammatory myofibroblastic tumor, anaplastic thyroid cancer, and in neuroblastoma were also detected [3, 4].

​

Lung cancer is the most commonly diagnosed malignancy and the leading cause of death from cancer in men worldwide. In the United States, more patients die from lung cancer every year than combined prostate, breast and colon cancer [5]. Lung cancer accounted for 11.6%, or 2,093,876 of all cancer cases worldwide in both sexes, causing 18.4%, or 1,761,007 of all disease-related deaths in 2018 [6]. Therefore, the development of new therapeutic strategies to cope with the disease is critical.

​

Lung cancer can be classified histologically into two main groups: non-small-cell lung cancer (NSCLC) and small cell lung cancer (SCLC), representing 85% and 15% of lung cancer cases, respectively. The NSCLC is further divided into three different subgroups: squamous cell carcinoma, adenocarcinoma and large cell carcinoma [7]. Generally, patients with NSCLC are diagnosed with the disease in advanced stages, and the mean survival time after diagnosis is usually less than one year [8], is associated with a survival rate of only 22% with conventional chemotherapy treatment.

​

Several genomic alterations play an essential role in the tumor progression of NSCLC: epidermal growth factor receptor (EGFR), KRAS, BRAF and MET, ALK and ROS1 [9]. Most patients with NSCLC with modified ALK expression are generally younger, and the cells have adenocarcinoma histology, thus presenting a severe clinical condition, since the disease is frequently diagnosed in advanced stages, making a practical therapeutic approach difficult.

​

Crizotinib is an oral-use tyrosine kinase receptor inhibitor developed in 2007 by Pfizer, La Jolla Laboratories. Crizotinib was developed initially as a selective inhibitor directed to the growth factor of mesenchymal-epithelial transition (c-MET) [10]. However, it is widely active in several therapeutic targets, including ALK, Hepatocyte Growth Factor Receptor (HGFR, c-Met), Recepteur d'Origine Nantais (RON), and ROS1 [11, 12].

​

Crizotinib was approved by the Food and Drug Administration (FDA) for the first-line treatment of advanced NSCLC disease positive for ALK mutation in 2013 and approved by the European Medicines Agency (EMA) for the same indication in November 2015. Since its discovery, crizotinib entered the phase I clinical studies that reported 72% of tumor progression-free survival, with an overall response of 57% in NSCLC positive for ALK [13]. The encouraging results soon enabled the use of crizotinib to be expanded as a specific therapeutic drug for patients with NSCLC. The FDA had initially approved the use of the drug for NSCLC patients with ALK mutations; the new approval also included patients with ROS1 gene mutations, also found in NSCLC. Clinical trials demonstrated that among patients with ROS1 gene mutations 6% had a complete response, 66% had a partial response, and 18% had stable disease as their best response. The global response rate was 72%, that is a very positive result [14].

​

Crizotinib is well tolerated and leads to significant improvements in efficacy and quality of life in patients not treated or previously treated with conventional chemotherapy. The discovery of the rearrangements of the ALK and ROS1 gene in the progression of the NSCLC and the development of crizotinib as a targeted drug have tremendously transformed the advanced NSCLC treatment landscape and paved the way for the development of new therapeutic strategies.

​

The development of crizotinib was a significant advance in first-generation cancer-specific therapies. With the progress of research, new ALK-inhibiting molecules and other tyrosine kinases are under investigation, increasing the therapeutic possibilities for the treatment of NSCLC and other cancers. Ceritinib was the second-generation tyrosine kinase inhibitor developed for the treatment of ALK-positive NSCLC. Compared to crizotinib, ceritinib is 20 times more potent in inhibiting ALK [15]. Alectinib is another highly selective inhibitor of ALK for patients who present resistance to treatment with crizotinib [16]. Alectinib obtained accelerated FDA approval in December 2015. The development of inhibitors directed to tyrosine kinases from crizotinib are being tested in several tumors such as inflammatory myofibroblastic tumor [17], brain metastases [18, 19], renal cell carcinoma [20], large cell anaplastic lymphoma [21], and neuroepithelial tumor [22]. Progressively, the development of new inhibitors will increase our possibility of undergoing targeted treatment against cancer.

​

The long years of research with the discovery of mutations in the ALK produced significant advances in the treatment of advanced lung cancer. However, these gene mutations are present in many other diseases. Fortunately, we have progressed in the development of tyrosine kinases inhibitors with antitumor activity, particularly in the treatment of lung cancer. The study and application of these tyrosine kinases inhibitors are being expanded in the treatment of other malignancies, with more specificity against the disease and with fewer side effects than conventional chemotherapy, improving the recovery and quality of life of patients.