Researchers at Severance Hospital have found that suppressing yes-associated protein 1 (YAP) gene expression is effective in treating refractory anaplastic lymphoma kinase (ALK) fusion-positive lung cancer is effective.
|Professors Cho Byoung-chul (left) and Yoon Mi-ran|
ALK-positive lung cancer accounts for 3 to 7 percent of all lung cancer and occurs mainly in younger adenocarcinoma patients who have never smoked. Although hospitals use first-generation ALK tyrosine kinase inhibitor (ALK-TKI) as a primary treatment, it is difficult to treat them due to resistance problems occurring within one or two years of treatment.
ALK is resistant to anticancer agents by generating secondary mutations (ALK dependent mechanisms) or bypass signaling pathways involved in cancer cell growth and metastasis (ALK independent mechanisms). Next-generation ALK inhibitors can control such mutations, but nothing can treat ALK-independent mechanisms.
The team, led by Professors Cho Byoung-chul and Yoon Mi-ran, identified a new target for overcoming anticancer drug resistance by conducting a drug repositioning strategy to screen 640 drugs approved by the U.S. Food and Drug Administration.
The drug repositioning strategy is a method for developing new drugs used or developed through clinical trials but does not apply to the actual clinical field. As a result, statin, a cholesterol-lowering agent, showed a robust antitumor effect on the anticancer drug resistance model. Statin showed that it is closely associated with the metabolite blockage that triggers the activity of YAP, a transcriptional regulator of cancer genes.
The team also identified YAP activity in resistant cells, patient-derived xenografts, and transgenic mice that exhibited actual ALK-independent resistance.
To identify the possibility of YAP as a new target in ALK lung cancer, the team removed YAP from a model of ALK inhibitor-resistant lung cancer. They found that it showed a statin-like antitumor effect.
The researchers also saw an inhibition in the expression of resistant factors, such as epidermal growth factor receptor and AXL receptor tyrosine kinase, in ALK lung cancer reported so far.
On the contrary, artificially overexpressing YAP in the ALK lung cancer model that is responsive to ALK inhibitors showed resistance to ALK inhibitors, along with the induction of resistance-induced gene expression.
To validate the clinical efficacy, the team evaluated YAP gene expression patterns on pre and post-tumor biopsies from 17 ALK-positive lung cancer patients. As a result, the YAP gene was more distributed in the nucleus of cancer cells after chemotherapy.
"We were able to confirm that the ALK-TKI's resistance mechanism accumulates YAP genes accumulate in the nucleus through various preclinical models, including cell, animal, and patient samples," Professor Yoon said. "Notably, the research is significant as it demonstrates the possibility of integrating the complex resistance mechanisms of ALK inhibitors reported so far through YAP activity regulation."
Professor Cho also said, "In the case of ALK-TKI-resistant lung cancer, despite the various studies, the rationale for the factors that can be treated was unclear."
The study suggests the possibility of developing new targeted therapies for ALK-TKI lung cancer, he added.
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