A research group at Kanazawa University, including Assistant Professor Koji Fukuda from the Cancer Research Institute and Nano Life Science Institute, Lecturer Shinji Takeuchi from the Department of Medical Oncology at University Hospital and Nano Life Science Institute, and Professor Seiji Yano from the Department of Respiratory Medicine, Nano Life Science Institute and Cancer Research Institute, has successfully developed a new treatment targeting WEE1 (*2) protein for lung cancer with KRAS (*1) gene mutation (KRAS lung cancer).
Lung cancer is the leading cause of cancer-related deaths in Japan, with KRAS mutations detected in approximately 10% of Japanese patients with lung adenocarcinoma. These mutations are known to promote cancer development and progression strongly. Recently, a KRAS-G12C inhibitor has been approved in Japan for lung cancer treatment. However, its efficacy is limited, and resistance remains a significant challenge, highlighting the urgent need for more effective therapies.
In this study, the research group explored 746 genes in KRAS mutant lung cancer by experimentally disrupting them and identified the molecule WEE1 as a new therapeutic target. Furthermore, they confirmed that combining a WEE1 inhibitor and a KRAS-G12C inhibitor is a highly promising treatment for KRAS-G12C lung cancer, particularly in cases where a TP53 mutation coexists. The combination therapy demonstrated remarkable effectiveness in almost completely eliminating lung cancer cells.
These findings not only offer a new treatment option for KRAS lung cancer but also bring hope for improved survival rates, especially in cases where the efficacy of KRAS inhibitors alone is limited.
The results of this research were published online in the international journal Cell Reports Medicine on May 21, 2024 at 11:00 a.m. EST.
Figure 1: The results of 746 comprehensive gene disruption experiments in two KRAS lung cancer cell lines showed that disruption of the WEE1 gene was the strongest inhibitor of cancer cell survival.
Figure 2: In an experiment using a mouse model (PDX model), cancer tissue from a lung cancer patient with a KRAS-G12C mutation was transplanted into mice. The combination treatment with the two drugs resulted in almost complete tumor disappearance.
Figure 3: Mechanism of action of the two-drug combination. The first drug (a KRAS-G12C inhibitor) damages the cancer cells' DNA. However, the cancer cells can repair this damage using WEE1 and survive (left figure). The simultaneous use of the second drug, a WEE1 inhibitor, stops this repair process, resulting in the death of the cancer cells (right figure).
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*1: KRAS
KRAS is a protein that regulates cell growth and division. However, when the KRAS gene is mutated, cells grow uncontrollably and cause cancer. In particular, KRAS mutations have been implicated in lung, colon, and pancreatic cancers.
*2: WEE1
WEE1 is a protein that regulates the cell cycle, the process by which cells grow and divide. When WEE1 does not function properly, damaged cells may continue to divide without repair, resulting in cell death.
Click here to see the press release【Japanese only】
Journal：Cell Reports Medicine
Researcher's Information: Koji Fukuda
Shinji Takeuchi
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