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Targeting brain metastases in ALK-rearranged non-small-cell lung cancer
Isabella Zhang1, Nicholas G Zaorsky2, Joshua D Palmer3
1Department of Radiation Medicine, North Shore-Long Island Jewish Health System, Lake Success, NY, USA.
Abstract:
The incidence of brain metastases has increased as a result of improved systemic control and advances in imaging. However, development of novel therapeutics with CNS activity has not advanced at the same rate. Research on molecular markers has revealed many potential targets for antineoplastic agents, and a particularly important aberration is translocation in the ALK gene, identified in non-small-cell lung cancer (NSCLC). ALK inhibitors have shown systemic efficacy against ALK-rearranged NSCLC in many clinical trials, but the effectiveness of crizotinib in CNS disease is limited by poor blood-brain barrier penetration and acquired drug resistance. In this Review, we discuss potential pathways to target ALK-rearranged brain metastases, including next generation ALK inhibitors with greater CNS penetration and mechanisms to overcome resistance. Other important mechanisms to control CNS disease include targeting pathways downstream of ALK phosphorylation, increasing the permeability of the blood-brain barrier, modifying the tumour microenvironment, and adding concurrent radiotherapy.
Insights
Targeting anaplastic lymphoma kinase (ALK)-rearranged brain metastases is crucial. Next-generation ALK inhibitors and combination therapies show promise for improving outcomes in non-small-cell lung cancer patients with brain metastases.
Area of Science:
- Oncology
- Neuro-oncology
- Pharmacology
Background:
- Brain metastases incidence is rising due to improved cancer care and imaging.
- Therapeutic development for central nervous system (CNS) disease lags behind systemic treatments.
- Anaplastic lymphoma kinase (ALK) gene rearrangements are key targets in non-small-cell lung cancer (NSCLC).
Purpose of the Study:
- To review strategies for targeting ALK-rearranged brain metastases.
- To explore novel therapeutics and resistance mechanisms for CNS disease.
Main Methods:
- Review of current literature on ALK inhibitors and CNS penetration.
- Discussion of resistance mechanisms and potential therapeutic targets.
- Exploration of combination strategies including radiotherapy.
Main Results:
- Crizotinib's efficacy in CNS disease is limited by poor blood-brain barrier (BBB) penetration and resistance.
- Next-generation ALK inhibitors offer improved CNS penetration.
- Targeting downstream pathways and the tumor microenvironment are potential strategies.
Conclusions:
- Developing effective treatments for ALK-rearranged brain metastases requires overcoming BBB limitations and drug resistance.
- Combination approaches, including novel inhibitors and radiotherapy, are essential for managing CNS disease in NSCLC.
