ALK Inhibitors-Pipeline Insights

• Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase (RTK) that belongs to the super-family of insulin receptor (IR).
• The ALK gene in humans encodes ALK, and immunohistochemical analysis reveals that ALK expression is partially scattered in neural cells, pericytes and endothelial cells in the brain of adult human tissues.
• ALK mRNA is also found to be expressed in the small intestine, prostate, testis, and colon. ALK was initially identified as the product of a gene rearrangement in the case of anaplastic large cell lymphoma (ALCL).
• ALK was eventually found to be rearranged, mutated, or amplified in a series of tumors including non-small cell lung cancer (NSCLC), inflammatory myofibroblastic tumors, diffuse large B cell lymphoma, renal cell carcinoma, colon cancer, breast carcinoma neuroblastoma, and esophageal cancer.
• The marketed ALK inhibitors currently in the market include Zykadia (ceritinib) and Alecensa (alectinib) that are indicated for the treatment of gastrointestinal cancer and non-small cell lung cancer.
• The ALK inhibitors pipeline includes more than 15 molecules, and they are expected to achieve regulatory approval shortly, few of which include – dasatinib (X-396), CEP-28122, X-376, X-390, EBI-600215. Recently in the last few years, novel potent ALK inhibitors have become available with promising results and a good toxicity profile that includes ceritinib (LDK378), brigatinib (AP26113), entreating (RXDX-101).
• The theories and practices of individualized cancer therapy have significantly influenced the approval of the first-generation ALK inhibitor, crizotinib (XalkoriTM; Pfizer), by the US FDA.
• Second-generation ALK inhibitors (ceritinib [Zykadia], alectinib [Alectinib], and brigatinib [Alunbrig]) were developed to increase anti-ALK activity, to overcome crizotinib-resistant mutations and to improve their business in CNS disease. 
• Crizotinib has become the reference treatment for ALK+ NSCLC patients and a promising treatment for tumors. Unfortunately, many patients have developed acquired resistance in the first year of treatment, and thus its efficacy is limited to CNS disease. Therefore strategies urgently have to be designed to overcome inherent and acquired resistance of using ALK inhibitors.
• Nowadays, several second-generation ALK inhibitors are under various stages of clinical development that are showing activity in crizotinib-resistant disease with promising activity in CNS disease patients. The third-generation (such as erlotinib) ALK inhibitors also came into existence in patients with CNS involvement.
• The goal of increasing inhibitory activity against ALK and defeating the inevitable development of drug resistance add fuel to the emergence of new ALK inhibitors.
• The procedure of resistance presents the need for new collaborations and education within the multi-disciplinary team. In the sequence of generalized progression, an understanding of the present molecular mechanism of resistance is evolved as a key to decision-making and clinical management that highlights the role of the pathologist.
• The strong clinical evidence showed that ALK is one a key driving factor of oncogenesis, which will make it a key drug target. A key challenge is to understand that why ALK-positive patients are not getting benefit from checkpoint inhibition and the need to develop new therapeutic strategies to effectively tackle the immune system to identify ALK-positive cancers.