Construction of a Resistance Response Map for Targeted Therapies in Lung Cancer

Analysis of Over 3,000 ALK Gene Mutations in Non-Small Cell Lung Cancer

The cause of resistance to targeted therapies in lung cancer patients with ALK gene mutations has been identified.

A research team led by Professor Kim Hyungbum, along with instructors Oh Hyungchul and Han Yeonseung, and Dr. Jang Yujin from the Department of Pharmacology at Yonsei University College of Medicine, announced on March 5 that they have constructed a resistance map for targeted therapies by functionally analyzing most of the possible mutations in the tyrosine kinase domain of the ALK gene, which is known to be a major cause of non-small cell lung cancer.

Yonsei Medical Center

This research was published in the international journal Genome Biology (IF 9.4).

ALK gene fusion is known to be a major cause of non-small cell lung cancer, accounting for about 5% of patients. The introduction of targeted therapies has dramatically improved treatment outcomes for patients; however, drug resistance typically develops within 1 to 2 years of use, resulting in cancer recurrence, which continues to be reported as a problem.

In particular, acquired resistance mutations, which are a major cause of drug resistance, are only partially addressed in current clinical guidelines, making it difficult to predict drug responses to the wide variety of mutations actually found in clinical settings. In addition, there is a lack of systematic data on resistance mechanisms to drugs after third-generation therapies, as well as on mutation responses to next-generation therapies.

The research team used prime editing, a next-generation gene editing technology, to introduce 3,208 mutations—representing approximately 99% of possible single nucleotide variants—in the ALK tyrosine kinase domain (exons 20 to 28) into lung cancer cell lines. They then treated these cells with second-generation alectinib, third-generation lorlatinib, and fourth-generation zoticilib, respectively, analyzing the drug sensitivity of each mutation to these therapies and quantifying the results to establish a 'functional atlas.'

Through this 'functional atlas,' the research team was able to identify not only the major resistance mutations to drugs that were previously known, but also potential mutations, thereby securing data that allows for quantitative comparison of drug responses by mutation.

Furthermore, by combining drug resistance scores for each mutation with modeling based on protein 3D structures, they confirmed that not only mutations within the drug binding site, but also those located structurally distant from the binding site, can interfere with targeted drug binding and induce resistance. These mutation-specific response data are expected to serve as important evidence in interpreting genetic test results and determining whether a specific mutation is indeed the cause of drug resistance in patients.

Professor Kim Hyungbum stated, "This study is significant in that it systematically analyzed drug responses to ALK mutations and established a functional map," adding, "We expect it will play an important role in developing precision medicine-based treatment strategies and in new drug development research in the future."

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