An ALK inhibitor is a type of targeted cancer therapy. These medications block the activity of the anaplastic lymphoma kinase (ALK) protein. This approach targets cancers with a genetic rearrangement involving the ALK gene. By interfering with ALK function, these inhibitors hinder cancer cell growth and spread.
The Role of the ALK Gene in Cancer
The anaplastic lymphoma kinase (ALK) gene creates the ALK protein, which regulates cell growth and division by transmitting signals.
In certain cancers, the ALK gene abnormally fuses with another gene. This involves a chromosomal translocation, where genetic material is exchanged. For instance, in non-small cell lung cancers, ALK often joins with the EML4 gene, while in anaplastic large cell lymphoma, it can fuse with the NPM gene.
This genetic rearrangement results in a faulty, continuously active ALK protein, sending constant growth signals. This unchecked signaling promotes abnormal cancer cell growth and survival, driving tumor formation.
Mechanism of Action
ALK inhibitors counteract aberrant signaling from the faulty ALK protein. They bind to the active site of the abnormal ALK protein. This prevents the protein from transmitting continuous growth signals.
Types of ALK Inhibitors
ALK inhibitors have progressed through generations, improving potency, overcoming resistance, and brain delivery. Crizotinib, a first-generation ALK inhibitor, is approved for ALK-positive non-small cell lung cancer and targets ROS1 and c-MET.
Second-generation ALK inhibitors include alectinib, brigatinib, and ceritinib. These agents are more potent than crizotinib and better penetrate the blood-brain barrier, which is important for brain metastases.
Lorlatinib, a third-generation ALK inhibitor, addresses acquired resistance to earlier drugs. It is effective against resistance mutations like the common G1202R, which can render previous inhibitors less effective. While effective in prolonging progression-free survival, lorlatinib may have more pronounced side effects.
Common Side Effects and Management
ALK inhibitors can cause side effects. Common effects include fatigue, nausea, vomiting, diarrhea, and vision disturbances.
These are often manageable with supportive care. More serious, less frequent effects include liver problems or lung inflammation (pneumonitis). Regular monitoring via blood tests and imaging helps detect issues. Patients should report any new or worsening symptoms to their doctors for appropriate management.
Acquired Resistance
Cancer cells can develop “acquired resistance” to ALK inhibitors. This occurs when cancer cells evolve genetic mutations bypassing the drug’s action.
When resistance is suspected, a biopsy analyzes the tumor for specific resistance mutations. Patients may then switch to a different, newer-generation ALK inhibitor. This approach aims to control cancer despite resistance.