American Association for Cancer Research
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Supplementary Figure 1 from TAS0612, a Novel RSK, AKT, and S6K Inhibitor, Exhibits Antitumor Effects in Preclinical Tumor Models

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journal contribution
posted on 2024-02-01, 08:41 authored by Koji Ichikawa, Satoshi Ito, Emi Kato, Naomi Abe, Takumitsu Machida, Junya Iwasaki, Gotaro Tanaka, Hikari Araki, Kentaro Wakayama, Hideki Jona, Tetsuya Sugimoto, Kazutaka Miyadera, Shuichi Ohkubo

Supplementary Figure 1. Body weight change of each treatment group corresponding to each efficacy study shown in Fig. 6B-6E are shown in panel A-D, respectively. In all studies, there was no evidence of intolerance, such as rapid and severe weight reduction. The weight on Day 0 was defined as 100%, and the increase or decrease in weight of each group on each measurement day relative to the weight on Day 0 is shown as a percentage (mean ± standard error).





The MAPK and PI3K pathways are involved in cancer growth and survival; however, the clinical efficacy of single inhibitors of each pathway is limited or transient owing to resistance mechanisms, such as feedback signaling and/or reexpression of receptor-type tyrosine kinases (RTK). This study identified a potent and novel kinase inhibitor, TAS0612, and characterized its properties. We found that TAS0612 is a potent, orally available compound that can inhibit p90RSK (RSK), AKT, and p70S6K (S6K) as a single agent and showed a strong correlation with the growth inhibition of cancer cells with PTEN loss or mutations, regardless of the presence of KRAS and BRAF mutations. Additional RSK inhibitory activity may differentiate the sensitivity profile of TAS0612 from that of signaling inhibitors that target only the PI3K pathway. Moreover, TAS0612 demonstrated broad-spectrum activity against tumor models wherein inhibition of MAPK or PI3K pathways was insufficient to exert antitumor effects. TAS0612 exhibited a stronger growth-inhibitory activity against the cancer cell lines and tumor models with dysregulated signaling with the genetic abnormalities described above than treatment with inhibitors against AKT, PI3K, MEK, BRAF, and EGFR/HER2. In addition, TAS0612 demonstrated the persistence of blockade of downstream growth and antiapoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent reexpression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for patients with cancer to improve clinical responses and overcome resistance mechanisms.