, /PRNewswire/ – Researchers at Nano Life Science Institute (WPI-NanoLSI) and the Cancer Research Institute at Kanazawa University led have uncovered how targeted lung cancer drugs alter the shape and behavior of a key cancer-driving protein—revealing a hidden mechanism that helps explain why some treatments stop working over time.

Targeted cancer therapies are designed to block specific molecules that drive tumor growth. One such molecule, ALK, plays a central role in a form of lung cancer caused by a genetic fusion known as EML4–ALK. Drugs that inhibit ALK have dramatically improved patient outcomes, but many patients eventually develop resistance, limiting long-term effectiveness.

Until now, it has been difficult to understand this resistance at a molecular level because large parts of the EML4–ALK protein are highly flexible and constantly changing shape, making them difficult to analyze using conventional structural biology techniques.

Watching cancer proteins move, one molecule at a time

In this study, Seijo Yano from the Nano Life Science Institute (WPI-NanoLSI) and colleagues at the Cancer Research Institute at Kanazawa University used high-speed atomic force microscopy (HS-AFM) to directly observe individual EML4–ALK proteins in real time.

This approach allowed the team to watch how the protein repeatedly assembles and disassembles into small clusters and how these movements change when cancer drugs are added. Among several variants of EML4–ALK, one clinically important form—known as variant 3—showed especially complex and unstable behavior.

The researchers discovered a previously unknown structural element within a flexible region of the protein that briefly forms a compact shape and strongly influences how the protein clusters. This structural feature was found in variant 3, which is known to respond less favorably to treatment in patients.

Cancer drugs reshape protein structure—and resistance blocks this effect

The study also revealed that commonly used ALK inhibitors do more than simply suppress enzyme activity. These drugs physically reshape the flexible regions of the protein, reducing its ability to form clusters that drive cancer signaling.

However, this structural effect was lost when the protein carried a well-known drug-resistance mutation (ALK G1202R), providing a direct structural explanation for why certain tumors become unresponsive to treatment.

"Our results show that ALK inhibitors work not only by blocking kinase activity, but also by altering the overall structure of the cancer-causing protein," says Yano, who led the study. "This long-range structural effect disappears in drug-resistant mutants, which may be one reason why resistance emerges in clinical settings."

Toward better strategies against drug resistance

By directly visualizing how cancer drugs alter protein structure at the single-molecule level, this research provides new insight into why different patients respond differently to the same therapy. The findings suggest that future drug development could benefit from targeting not only enzyme activity, but also the structural dynamics of oncogenic fusion proteins.

This work highlights the unique power of high-speed AFM to reveal molecular behaviors that are otherwise inaccessible and opens new avenues for designing next-generation therapies for ALK-driven lung cancer.

Related figures:

Fig.1 https://nanolsi.kanazawa-u.ac.jp/wp/wp-content/uploads/Fig.1en_ACS-Nano_Jan.2026.jpg Caption: Compaction of the EML4 region by ALK inhibitor alectinib and its cancellation by ALKG1202R resistance mutation.

Fig.2 https://nanolsi.kanazawa-u.ac.jp/wp/wp-content/uploads/Fig.2en_ACS-Nano_Jan.2026.jpg Caption: Schema of three EML4-ALK variants observed by HS-AFM.

All three variants demonstrated dynamic, reversible transitions between monomeric, dimeric, and trimeric states. We identified a previously uncharacterized TFG subdomain within the EML4 that may be causally linked to the diverse patterns of oligomerization observed for the ALK domains. Conversely, ALK inhibitors such as alectinib compacted the EML4 and suppressed EML4-ALK oligomerization, providing a molecular basis for its activity.

Credits: All figures were created by the authors based on data from Xujun Han et al. (2026).

Reference

High-Speed Atomic Force Microscopy Reveals Disordered Region–Mediated Structural Plasticity of Anaplastic Lymphoma Kinase Fusion Proteins Induced by Inhibitors,

Xujun Han, Noriyuki Kodera, Neval Yilmaz, Katsuya Sakai, Sachiko Arai, Borui Li, Ryu Imamura, Dominic Chih-Cheng Voon, Koji Fukuda, Shigeki Nanjo, Holger Flechsig, Hiroyuki ManoKunio Matsumoto, Seiji Yano, ACS Nano, January 20, 2026.

https://doi.org/10.1021/acsnano.5c17078

Acknowledgements

The authors thank Toshio Ando (Kanazawa University) for technical support and guidance in high-speed atomic force microscopy. They also acknowledge Yumiko Tahira and Nawaphat Jangphattananont (Kanazawa University) for technical assistance with protein purification.

This research was supported by the Collaborative Research Grant of the Nano Life Science Institute, Kanazawa University, the Kanazawa University Hospital SAKIGAKE Project (2022), the Extramural Collaborative Research Grant of the Cancer Research Institute, Kanazawa University, Boehringer-Ingelheim, and JSPS KAKENHI (Grant Numbers 20K22837 and 22K07208).

**Contact **

Kimiko Nakazaki (Ms) Project Planning and Outreach, NanoLSI Administration Office Nano Life Science Institute, Kanazawa University Email: [email protected] Kakuma-machi, Kanazawa 920-1192, Japan

Nano Life Science Institute (WPI-NanoLSI), Kanazawa University

Understanding nanoscale mechanisms of life phenomena by exploring "uncharted nano-realms." Cells are the basic units of life. At NanoLSI, researchers develop nanoprobe technologies that enable direct imaging, analysis, and manipulation of biomolecules such as proteins and nucleic acids inside living cells. By visualizing these processes at the nanoscale, the institute seeks to uncover fundamental principles of life and disease.

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About Kanazawa University

Founded in 1862 in Ishikawa Prefecture, Kanazawa University is one of Japan’s leading comprehensive national universities with a history spanning more than 160 years. With campuses at Kakuma and Takaramachi–Tsuruma, the university upholds its guiding principle of being "a research university dedicated to education, while opening its doors to both local and global society."

Internationally recognized for its research institutes, including the Nano Life Science Institute (WPI-NanoLSI) and the Cancer Research Institute, Kanazawa University promotes interdisciplinary research and global collaboration, driving progress in health, sustainability, and culture.

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