Researchers Find Vulnerability in Metabolism That Drives Lung Cancer Growth

Researchers from Mass General Brigham worked with a team to identify an enzyme that boosts cancer cell metabolism to fuel growth in a subset of lung cancers. Their findings, published in Cell, used mouse models and human cancer cells to uncover the role of the enzyme GUK1 in ALK-positive lung cancer. The metabolic reliance on GUK1 is a vulnerability that new therapeutics can potentially target to curb cancer growth.

“A huge percentage of patients I see in the clinic do well for some time on the currently available therapies, but eventually relapse,” said lead author of the study Jaime Schneider, MD, PhD, of the Mass General Cancer Center, a member of Mass General Brigham. “We need to think outside the box to better understand lung cancer's disease biology and identify new therapeutic targets.” 

The team is working to understand how cancer cells change their metabolism to evade attacks by the immune system and cancer treatments in ALK-positive lung cancers, which produce an abnormal ALK protein. They determined that the GUK1 enzyme helps the abnormal ALK proteins make a precursor for the energy-rich molecules that cancer cells rely on to divide and produce proteins. When the researchers disabled GUK1, cancer cell growth slowed considerably, suggesting that ALK-positive cancers become highly dependent on this enzyme as their molecular fuel.

“GUK1 turned out to be a metabolic liability in this subset of lung cancer that facilitates tumor growth and survival,” Schneider said.

The team hopes that identifying specific metabolic vulnerabilities, like GUK1, will help to pave the way for new therapeutic approaches and address resistance to targeted therapies in ALK-positive lung cancers and those driven by other genetic defects.

Authorship: In addition to Schneider, Mass General Brigham authors include Toshio Fujino, Satoshi Yoda, Gerard Baquer, Daniela Ruiz, Sylwia A. Stopka, Andrew Do, Mari Mino-Kenudson, Lecia V. Sequist, Jessica J. Lin, Nathalie Y.R. Agar, and Aaron N. Hata. Other authors include Kiran Kurmi, Yutong Dai, Ishita Dhiman, Shakchhi Joshi, Brandon Gassaway, Christian W. Johnson, Nicole Jones, Zongyu Li, Christian P. Joschko, Joao A. Paulo, Liam Kelley, Steven P. Gygi, Kevin M. Haigis, Marcia C. Haigis.

Disclosures: Schneider has received honoraria from the Academy of Continued Healthcare Learning, Springer Healthcare, Targeted Oncology, Total Health Conferencing, DAVA Oncology, Physicians’ Education Resource; travel from Dava Oncology; research funding from Gilead. Additional disclosures can be found in the paper.

Funding: The study was funded by the National Institutes of Health (R01CA240317; R01CA164273), the National Institutes of General Medical Sciences (R01GM132129; GM67945), the National Cancer Institute (R01CA273461; U01CA267827), the Joslin Diabetes Center, the Ludwig Center at HMS, A Breath of Hope Lung Foundation, the Lung Cancer Research Foundation, an American Cancer Society Institutional Research Grant, the Life Sciences Research Foundation, and K12CA087723.

Paper cited: Schneider, J, et al. “GUK1 Activation is a Metabolic Liability in Lung Cancer” Cell DOI: 10.1016/j.cell.2025.01.024