ALK Targeted Therapy

ALK Targeted Therapy: Introduction

The anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase that is aberrant in a variety of malignancies. For example, activating missense mutations within full length ALK are found in a subset of neuroblastomas. By contrast, ALK fusions are found in anaplastic large cell lymphoma, colorectal cancer, inflammatory myofibroblastic tumor non-small cell lung cancer, and ovarian cancer. All ALK fusions contain the entire ALK tyrosine kinase domain. To date, those tested biologically possess oncogenic activity in vitro and in vivo. ALK fusions and copy number gains have been observed in renal cell carcinoma. Finally, ALK copy number and protein expression aberrations have also been observed in rhabdomyosarcoma.
The various N-terminal fusion partners promote dimerization and therefore constitutive kinase activity. Signaling downstream of ALK fusions results in activation of cellular pathways known to be involved in cell growth and cell proliferation.

More recently, in 2007 a translocation in the gene encoding the receptor tyrosine kinase anaplastic lymphoma kinase (ALK),
leading to the expression of ALK fusion proteins, was identified as an oncogenic driver in a subset of patients with non small cell lung cancer. ALK rearrangements are found in approximately 3% of unselected patients with NSCLC. ALK-positive non small cell lung cancer has been associated with a younger patient population than that associated with EGFR mutations and that associated with wild-type ALK and EGFR. ALK positive patients are also generally never-smokers or are light smokers, and predominantly have adenocarcinoma. Data indicating the prognosis of patients with ALK-positive non small cell lung cancer compared to ALK-negative non small cell lung cancer are inconclusive. As ALK tyrosine kinase is required for oncogenesis, inhibition by a tyrosine kinase inhibitor should provide therapeutic efficacy.

Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK)-positive (ALK+ ALCL) is an aggressive CD30-positive T-cell lymphoma that exhibits a chromosomal translocation involving the ALK gene and the expression of ALK protein. The challenges in studying new drugs in ALK+ anaplastic large cell lymphoma are disease rarity and high cure rate with standard chemotherapy. However, some patients do present with high risk disease and sub-optimal remissions. Nevertheless, the development of novel therapies targeting CD30 and ALK is a major advance in the treatment of anaplastic large cell lymphoma.