NIBIOHN, NCC identify new therapeutic target for gastric cancer — High-resolution phosphorylation signal analysis classifies patients into three subtypes

A research group led by Deputy Director Jun Adachi of the Center for Drug Design Research at the National Institute of Biomedical Innovation, Health and Nutrition (NIBIOHN), in collaboration with researchers at the National Cancer Center Japan and Kyoto University, has announced that they identified a new therapeutic target for gastric cancer through high-resolution phosphorylation signal analysis. The collaborative group developed a technique to characterize phosphorylation signals for each patient and confirmed that the patients can be classified into three subtypes. Through this they succeeded in discovering a new therapeutic target. The results are expected to contribute to the development of therapeutic methods and were published in the international journal Cell Reports on Oct. 1.

Gastric cancer is the third most common cancer in terms of incidence and mortality. Particularly, unresectable advanced gastric cancer has a very poor prognosis with a median survival of approximately 12 months. Meanwhile, only a limited number of molecularly targeted drugs are effective against advanced gastric cancer. As most molecularly targeted drugs used as anticancer agents act directly on proteins, information on the entire set of proteins (proteome) in cancer cells is useful to select the optimal treatment. In particular, analysis of phosphorylation signals is expected to find application in "cancer precision medicine" because various functions of cancer cells are regulated through phosphorylation modifications.

The research group previously developed a technique to analyze phosphorylation signals in small quantities of fresh-frozen endoscopic biopsy specimens. They reported differences in treatment responsiveness among patients before and after trastuzumab administration. In the present study, they improved their previous signal analysis method and analyzed phosphorylation signals in 127 specimens from untreated patients with gastric cancer. As a result, an average of 21,103 phosphorylation sites were successfully quantified for each sample. Of the samples, 35% were classified as subtype 1, in which "kinases regulating the cell cycle are activated," 15% as subtype 2, which is characterized by "epithelial−mesenchymal transition (EMT) features," and 50% as subtype 3, in which "oxidative phosphorylation is elevated."

Analysis of phosphorylation signals in nine patients with unresectable advanced gastric cancer after first-line treatment (chemotherapy), during second-line treatment, and at the time of progression showed that subtype 2 increased over the course of treatment and transformed to a more malignant nature that was poorly responsive to drugs. Mesenchymal cancer cells constituting subtype 2 are known to have a poor prognosis because they are resistant to chemotherapy, molecularly targeted therapy and immunotherapy and prone to metastasis. Therefore, they focused on AXL, a receptor tyrosine kinase activated in subtype 2.

Cultured gastric cancer cells were treated with each of two AXL inhibitors in combination with paclitaxel to examine if this drug combination has additive growth inhibitory effects. The addon effects of AXL inhibitors were observed only in cultured mesenchymal gastric cancer cells with high AXL activity. Moreover, the combination of an AXL inhibitor and paclitaxel suppressed tumor growth in tumor-bearing mice generated by transplantation of cultured mesenchymal gastric cancer cells. The analysis over time before and during treatment was shown to be important, as it can be used to track drug-induced cancer changes in individual patients and to identify target tyrosine kinases.

Adachi said, "We have spent about 6 years to develop a technology for precise monitoring of phosphorylation signals in the human body. The present study in patients with gastric cancer revealed dynamic changes in the cancer properties over the course of treatment, having led to the development of a new treatment strategy. Moving forward, we will expand our research beyond gastric cancer."