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From first to third generation: How have ALK inhibitors evolved to fight cancer?
In modern medicine, cancer treatments are constantly changing and developing. Especially in tumors driven by various genetic mutations, ALK inhibitors have shown remarkable effects. These drugs specifically target tumors with abnormal lymphoma kinase (ALK) mutations, such as the EML4-ALK translocation. As a class of tyrosine kinase inhibitors, ALK inhibitors work by inhibiting proteins related to abnormal proliferation of tumor cells.
All currently approved versions of ALK inhibitors work by binding to the ATP pocket of the abnormal ALK protein, thereby blocking its energy harvest and inactivating it.
As of 2020, more than 92 fusion partners have been discovered in ALK-positive non-small cell lung cancer (NSCLC), although most ALK-rearranged NSCLC are still dominated by EML4-ALK fusion. Each fusion partner may have multiple variations, depending on where the two genes are fused, which can have a significant impact on tumor response and patient prognosis.
Approved inhibitors
First generation
The first-generation ALK inhibitor is crizotinib, which was approved by the US FDA in August 2011 and is specifically designed for ALK-positive NSCLC. At that time, crizotinib was originally developed by Pfizer as a c-MET inhibitor, but its efficacy against ALK gradually emerged, so Pfizer turned its focus to this application and received full approval four years later. In the phase III clinical trial PROFILE 1007, crizotinib significantly improved the patient's tumor stabilization or shrinkage rate, reaching an effect of 90%.
Although crizotinib has excellent efficacy, it often causes drug resistance within one year due to its low penetration and unsatisfactory specificity, and its progression is common in the brain.
Second generation
With the success of first-generation drugs, there is an urgent need to develop second-generation inhibitors to improve penetration and the ability to target drug-resistant mutations. Novartis' Ceritinib was approved by the FDA in April 2014, showing good brain penetration and a significant progression-free survival advantage. Roche's alectinib was also approved in December 2015, particularly in patients who have progressed on crizotinib, eventually becoming a first-line treatment option in 2017. Similar to ceritinib, its brain penetration and efficacy have achieved satisfactory results.
In addition, Ariad and Takeda's Brigatinib were approved in April 2017 and have also shown activity against certain drug-resistant mutations.
Third generation
In 2018, Pfizer's Lorlatinib became the first third-generation inhibitor, designed for patients who have progressed after first- or second-generation inhibitors. Its giant loop structure specifically targets various refractory drug-resistant mutations, but tumors may eventually develop drug resistance, often through mechanisms such as compounding mutations or initiating alternative pathways.
Clinical Trial
Currently, there are some new ALK inhibitors undergoing clinical trials, such as ensartinib and entrectinib, which are expected to further advance the treatment of ALK-positive tumors.
These drugs not only target ALK mutations, but also abuse other pathways such as EGFR and HER2, showing multiple therapeutic potential.
Combined therapies under investigation
Faced with drug resistance in cancer cells, current research is seeking a variety of combination therapies. For example, inhibition of the MEK pathway, anti-EGFR/HER2 pathway, and anti-VEGF therapy have all shown good efficacy.
For example, the combination of anti-VEGF antibodies and ALK inhibitors can prevent tumor growth by normalizing the large blood vessel structure around the tumor.
With the continuous deepening of research on ALK inhibitors, how to fight cancer more effectively and prolong the survival of patients has become the focus of current treatment. The evolution of these drugs is not only an improvement in treatment, but also challenges our understanding of tumor resistance and its development. Will we find truly radical solutions in increasingly evolving treatments?
