Three decades of anaplastic lymphoma kinase: from physiological roles to cancer and immune evasion.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase with structural criteria shared among members of the insulin receptor subfamily. ALK plays crucial physiological roles such as in neural tissue development as well as in thinness and body weight regulation. In addition, ALK is a key driver of systemic inflammation that may lead to lethal sepsis. The oncogenic potential of ALK was first described in 1994 when 2 independent research groups discovered that ALK is aberrantly expressed in a rare aggressive subtype of T-cell lymphoma descriptively known as anaplastic large-cell lymphoma. Later, it was found that the aberrant expression of ALK extends to include other neoplasms such as non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumors, and others. In these neoplasms, ALK plays a central oncogenic role by upregulating the activity of a comprehensive network of upstream and downstream survival systems, which causes tumor cell survival and proliferation. The development of selective ALK inhibitors has led to paradigm shift in how ALK-expressing tumors, particularly non-small cell lung cancer, are treated. More recently, ALK has been implicated in disturbing the integrity of the immune system and sustaining immune evasion. In this review, we highlight 3 decades of ALK research, briefly discuss its physiological and pathological roles with a focus on cancer and immunity, and provide an update on the clinical utilization and mechanisms of resistance to ALK inhibitors.