ALK inhibitors in non-small cell lung cancer: crizotinib and beyond

Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39.

Abstract

The treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring chromosomal rearrangements of anaplastic lymphoma kinase (ALK) has been revolutionized by the development of crizotinib, a small molecule inhibitor of the tyrosine kinases ALK, ROS1, and MET. Resistance to crizotinib invariably develops, however, through a variety of mechanisms. In the last few years, a flurry of new and more potent ALK inhibitors has emerged for the treatment of ALK-positive NSCLC, including ceritinib (LDK378), alectinib (RO5424802/CH5424802), AP26113, ASP3026, TSR-011, PF-06463922, RXDX-101, X-396, and CEP-37440. Cancers harboring ALK rearrangements may also be susceptible to treatment with heat shock protein 90 inhibitors. This review focuses on the pharmacologic and clinical properties of these compounds, either as monotherapies or in combination with other drugs. With so many ALK inhibitors in development, the challenges of how these agents should be studied and ultimately prescribed are also discussed.

Publication types

  • Review

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use*
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / mortality
  • Crizotinib
  • Drug Discovery
  • Drug Resistance, Neoplasm
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • Humans
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism
  • Molecular Targeted Therapy
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Receptor Protein-Tyrosine Kinases / metabolism
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • HSP90 Heat-Shock Proteins
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyridines
  • Crizotinib
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • Receptor Protein-Tyrosine Kinases