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Ref Type Journal Article
PMID (26469692)
Authors Yu Y, Savage RE, Eathiraj S, Meade J, Wick MJ, Hall T, Abbadessa G, Schwartz B
Title Targeting AKT1-E17K and the PI3K/AKT Pathway with an Allosteric AKT Inhibitor, ARQ 092.
Journal Vol Issue Date Pages Journal Short Title
PloS one 10 10 2015 e0140479 PLoS One
URL
Abstract Text As a critical component in the PI3K/AKT/mTOR pathway, AKT has become an attractive target for therapeutic intervention. ARQ 092 and a next generation AKT inhibitor, ARQ 751 are selective, allosteric, pan-AKT and AKT1-E17K mutant inhibitors that potently inhibit phosphorylation of AKT. Biochemical and cellular analysis showed that ARQ 092 and ARQ 751 inhibited AKT activation not only by dephosphorylating the membrane-associated active form, but also by preventing the inactive form from localizing into plasma membrane. In endometrial PDX models harboring mutant AKT1-E17K and other tumor models with an activated AKT pathway, both compounds exhibited strong anti-tumor activity. Combination studies conducted in in vivo breast tumor models demonstrated that ARQ 092 enhanced tumor inhibition of a common chemotherapeutic agent (paclitaxel). In a large panel of diverse cancer cell lines, ARQ 092 and ARQ 751 inhibited proliferation across multiple tumor types but were most potent in leukemia, breast, endometrial, and colorectal cancer cell lines. Moreover, inhibition by ARQ 092 and ARQ 751 was more prevalent in cancer cell lines containing PIK3CA/PIK3R1 mutations compared to those with wt-PIK3CA/PIK3R1 or PTEN mutations. For both ARQ 092 and ARQ 751, PIK3CA/PIK3R1 and AKT1-E17K mutations can potentially be used as predictive biomarkers for patient selection in clinical studies.

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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
ARQ 751 ARQ 751 11 1
Miransertib Miransertib 22 2
Drug Name Trade Name Synonyms Drug Classes Drug Description
ARQ 751 ARQ-751|ARQ751 Akt Inhibitor (Pan) 22 ARQ 751 is an inhibitor of AKT1, AKT2, and AKT3, which may result in inhibition of the AKT/PI3K/MTOR pathway, thereby leading to tumor growth inhibition (PMID: 26469692).
Miransertib ARQ-092|ARQ092|ARQ 092 Akt Inhibitor (Pan) 22 Miransertib (ARQ092) is a pan-AKT inhibitor, resulting in inhibition of the PI3K/AKT signaling pathway and cell proliferation (PMID: 26469692, PMID: 31058421).
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
BRAF V600E PIK3CA H1047K melanoma sensitive Miransertib + Trametinib Preclinical - Pdx Actionable In a preclinical study, a melanoma patient-derived xenograft (PDX) model harboring BRAF V600E and PIK3CA H1047K was sensitive to the combination treatment of Miransertib (ARQ092) and Mekinist (trametinib), demonstrating a greater inhibition of tumor growth when compared to either agent alone (PMID: 26469692). 26469692
PIK3CA E545K breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA E545K was sensitive to ARQ 751 in culture, demonstrating inhibition of cell growth (PMID: 26469692). 26469692
PIK3CA H1047R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R demonstrated sensitivity to treatment with Miransertib (ARQ092) in culture, resulting in inhibition of cell proliferation (PMID: 26469692). 26469692
PIK3CA H1047R breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA H1047R demonstrated sensitivity to treatment with ARQ 751 in culture, resulting in inhibition of cell proliferation (PMID: 26469692). 26469692
PIK3CA E542K breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, a hormone breast cancer cell line harboring PIK3CA E542K was sensitive to Miransertib (ARQ092) in culture, demonstrating inhibition of cell growth (PMID: 26469692). 26469692
PIK3CA P539R PIK3CA H1047R breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, breast cancer cells harboring PIK3CA P539R and H1047R were sensitive to Miransertib (ARQ092) in culture, demonstrating inhibition of cell growth (PMID: 26469692). 26469692
PIK3CA P539R PIK3CA H1047R breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, ARQ 751 inhibited cell growth in a breast cancer cell line harboring PIK3CA P539R and H1047R in culture (PMID: 26469692). 26469692
PIK3CA R93W PIK3CA D350G PTEN R130G endometrial cancer sensitive Miransertib Preclinical - Pdx Actionable In a preclinical study, a patient-derived xenograft (PDX) model of endometrial cancer harboring PIK3CA D350G, PIK3CA R93W, and PTEN R130G was sensitive to Miransertib (ARQ092), demonstrating greater than 90% inhibition of tumor growth (PMID: 26469692). 26469692
PIK3CA E545K breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, treatment with Miransertib (ARQ092) resulted in growth inhibition in hormone receptor positive breast cancer cells harboring PIK3CA E545K in culture (PMID: 26469692). 26469692
PIK3CA K111N breast cancer sensitive ARQ 751 Preclinical - Cell culture Actionable In a preclinical study, a breast cancer cell line harboring PIK3CA K111N was sensitive to ARQ 751 in culture, demonstrating inhibition of cell growth (PMID: 26469692). 26469692
PIK3CA K111N breast cancer sensitive Miransertib Preclinical - Cell culture Actionable In a preclinical study, hormone receptor positive breast cancer cells harboring PIK3CA K111N were sensitive to Miransertib (ARQ092) in culture, demonstrating inhibition of cell growth (PMID: 26469692). 26469692