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ALK-positive lung cancer: a moving target
Jaime L Schneider1,2, Jessica J Lin1,2, Alice T Shaw3,4
1Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, USA.
Abstract:
Anaplastic lymphoma kinase (ALK) is a potent oncogenic driver in lung cancer. ALK tyrosine kinase inhibitors yield significant benefit in patients with ALK fusion-positive (ALK+) lung cancers; yet the durability of response is limited by drug resistance. Elucidation of on-target resistance mechanisms has facilitated the development of next-generation ALK inhibitors, but overcoming ALK-independent resistance mechanisms remains a challenge. In this Review, we discuss the molecular underpinnings of acquired resistance to ALK-directed therapy and highlight new treatment approaches aimed at inducing long-term remission in ALK+ disease.
Insights
Drug resistance limits the effectiveness of anaplastic lymphoma kinase (ALK) inhibitors in ALK-positive lung cancer. This review explores resistance mechanisms and new strategies for durable remission.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Anaplastic lymphoma kinase (ALK) is a key driver in a subset of lung cancers.
- ALK tyrosine kinase inhibitors (TKIs) are effective but face acquired drug resistance.
- Resistance mechanisms, both on-target and off-target, limit long-term patient benefit.
Purpose of the Study:
- To review the molecular mechanisms of acquired resistance to ALK-targeted therapies.
- To discuss the development of next-generation ALK inhibitors.
- To highlight novel therapeutic strategies for overcoming resistance in ALK-positive lung cancer.
Main Methods:
- Literature review of studies on ALK-positive lung cancer and TKI resistance.
- Analysis of molecular pathways involved in acquired resistance.
- Synthesis of current and emerging treatment approaches.
Main Results:
- On-target resistance mechanisms have been identified and addressed by newer inhibitors.
- ALK-independent resistance mechanisms present a significant challenge to durable responses.
- Understanding these diverse resistance pathways is crucial for therapeutic advancement.
Conclusions:
- Continued research into resistance mechanisms is essential for improving outcomes in ALK-positive lung cancer.
- Combination therapies and novel drug development are key to overcoming resistance.
- Achieving long-term remission requires a comprehensive approach to managing acquired resistance.
