Anaplastic Lymphoma Kinase (ALK) Inhibitors: New Cancer Breakthroughs for Lung Cancer

Abstract

Kinases have become clinically validated targets for cancer therapy since imatinib first launched ten years ago. Twelve small molecule kinase-targeting agents have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of cancer. It indicates that deregulation of protein kinase, for example by amplification, translocation or mutation, is considered as a promising strategy for targeted cancer treatment. Thus, drugs targeting abnormal kinase activity hold great promise as potential targeted treatments. A new translocation gene mutation in non-small-cell lung cancer (NSCLC) was recently discovered in 2007: an unusual protein encoded from a fusion gene of anaplastic lymphoma kinase (ALK) and echinoderm microtubule-associated protein-like 4 (EML-4). Due to the connection between the aberrant expression and activation of ALK with the onset and progression of ALK-related ALCL, neuroblastomas and NSCLC, several agents have been developed to target oncogenic ALK kinase for the treatment of cancer. This manuscript provides a comprehensive review of ALK inhibitors in clinical development, in particular crizotinib, which received FDA's accelerated approval for the treatment of NSCLC patients. Due to several point mutations, ALK(superscript L1196M) and ALK(superscript C1156Y), acquired crizotinib resistance, a number of second-generation ALK inhibitors against both wild-type and mutated resistant ALK, such as AP-26113, X-396 and CH5424802, will be also discussed. In summary, approval of gefitinib and erlotinib for the treatment of NSCLC patients opens up new door for personalized therapy. Thus the breakthrough success of crizotinib against EML4-ALK-positive NSCLC cancers takes only six years from bench to bedside and marks a new era of personalized therapy. It is believed that one or more small-molecule ALK inhibitors are expected to reach the market in the very near future.