Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data
- 13 May 2015
- journal article
- review article
- Published by S. Karger AG in Oncology Research and Treatment
- Vol. 38 (6), 291-298
- https://doi.org/10.1159/000430852
Abstract
Anaplastic lymphoma kinase (ALK) rearrangement is one of the oncogenes in non-small cell lung cancer (NSCLC) identified in 2007. The PROFILE trials demonstrated that patients with ALK-rearranged NSCLC can be successfully treated with crizotinib, and that crizotinib is superior to chemotherapy in both first- and second-line settings. Furthermore, next-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to harbor excellent efficacy for NSCLC patients with ALK rearrangement. However, it is known that many cases ultimately acquire resistance to ALK inhibitors. Some potential mechanisms of resistance to ALK inhibitors are as follows: ALK dominant resistance, such as secondary mutations and copy number gain in the ALK gene; activation of the bypass tracks, including EGFR, KRAS, KIT, MET, and IGF-1R. Furthermore, treatment strategies to overcome these resistance mechanisms have been proposed, and next-generation ALK inhibitors, agents which inhibit the bypass tracks, and heat shock protein 90 inhibitors are thought to be promising. Thus, clinical and pre-clinical evidence on the resistance mechanisms to ALK inhibitors and treatment strategies to overcome the resistance have been gradually obtained. Herein, we concisely review the current clinical and pre-clinical data regarding the mechanisms of resistance to ALK inhibitors and treatments to overcome such resistance.Keywords
This publication has 54 references indexed in Scilit:
- Crizotinib versus Chemotherapy in AdvancedALK-Positive Lung CancerThe New England Journal of Medicine, 2013
- Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non–Small Cell Lung CancerClinical Cancer Research, 2012
- Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung CancersScience Translational Medicine, 2012
- ALK Mutations Conferring Differential Resistance to Structurally Diverse ALK InhibitorsClinical Cancer Research, 2011
- A Novel ALK Secondary Mutation and EGFR Signaling Cause Resistance to ALK Kinase InhibitorsCancer Research, 2011
- Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALKProceedings of the National Academy of Sciences of the United States of America, 2011
- The Neuroblastoma-Associated F1174L ALK Mutation Causes Resistance to an ALK Kinase Inhibitor in ALK-Translocated CancersCancer Research, 2010
- Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung CancerThe New England Journal of Medicine, 2010
- Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase DomainPLoS Medicine, 2005
- Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to GefitinibThe New England Journal of Medicine, 2004