Targeting ALK: Precision medicine takes on drug resistance

Abstract

Anaplastic lymphoma kinase (ALK) is a validated molecular target in several ALK-rearranged malignancies, including non-small cell lung cancer. However, the clinical benefit of targeting ALK using tyrosine kinase inhibitors (TKI) is almost universally limited by the emergence of drug resistance. Diverse mechanisms of resistance to ALK TKIs have now been discovered, and these basic mechanisms are informing the development of novel therapeutic strategies to overcome resistance in the clinic. In this review, we summarize the current successes and challenges of targeting ALK. Significance: Effective long-term treatment of ALK-rearranged cancers requires a mechanistic understanding of resistance to ALK TKIs so that rational therapies can be selected to combat resistance. This review underscores the importance of serial biopsies in capturing the dynamic therapeutic vulnerabilities within a patient’s tumor and offers a perspective into the complexity of on-target and off-target ALK TKI resistance mechanisms. Therapeutic strategies that can successfully overcome, and potentially prevent, these resistance mechanisms will have the greatest impact on patient outcome.