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Ref Type Journal Article
PMID (37906695)
Authors Ichikawa K, Ito S, Kato E, Abe N, Machida T, Iwasaki J, Tanaka G, Araki H, Wakayama K, Jona H, Sugimoto T, Miyadera K, Ohkubo S
Title TAS0612, a novel RSK, AKT, and S6K inhibitor, exhibits antitumor effects in preclinical tumor models.
Journal Vol Issue Date Pages Journal Short Title
Molecular cancer therapeutics 2023 Oct 31 Mol Cancer Ther
URL
Abstract Text The mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (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 re-expression of receptor-type tyrosine kinases (RTKs). 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. Additionally, TAS0612 demonstrated the persistence of blockade of downstream growth and anti-apoptotic signals, despite activation of upstream effectors in the signaling pathway and FoxO-dependent re-expression of HER3. In conclusion, TAS0612 with RSK/AKT/S6K inhibitory activity may provide a novel therapeutic strategy for cancer patients to improve clinical responses and overcome resistance mechanisms.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN L320* endometrial cancer sensitive TAS0612 Preclinical - Cell line xenograft Actionable In a preclinical study, TAS0612 inhibited proliferation in an endometrial cancer cell line harboring PTEN L320* along with ERBB2 (HER2) R896H and FGFR2 S252W in culture and induced tumor regression in a cell line xenograft model (PMID: 37906695). 37906695
PTEN P89fs breast cancer sensitive TAS0612 Preclinical - Cell line xenograft Actionable In a preclinical study, TAS0612 inhibited proliferation in a breast cancer cell line harboring PTEN P89fs in culture and induced tumor regression in a cell line xenograft model (PMID: 37906695). 37906695
PTEN R142fs PTEN L265fs ovarian cancer sensitive TAS0612 Preclinical - Cell line xenograft Actionable In a preclinical study, TAS0612 inhibited proliferation in a clear cell ovarian cancer cell line harboring PTEN R142fs and L265fs, along with KRAS G13C and PIK3CA H1047Y, in culture and induced tumor regression in a cell line xenograft model (PMID: 37906695). 37906695
PTEN K6fs endometrial cancer sensitive TAS0612 Preclinical - Cell line xenograft Actionable In a preclinical study, TAS0612 inhibited proliferation in an endometrial cancer cell line harboring PTEN K6fs along with PIK3CA mutations in culture and induced tumor regression in a cell line xenograft model (PMID: 37906695). 37906695