Reference Detail

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 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 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 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