Reference Detail

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	24	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ARQ 751		ARQ-751\|ARQ751	Akt Inhibitor (Pan) 21	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) 21	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
TSC2	L604P	missense	unknown	TSC2 L604P does not lie within any known functional domains of the Tsc2 protein (UniProt.org). L604P has been identified in sequencing studies (PMID: 26469692), but has not been biochemically characterized and therefore, its effect on Tsc2 protein function is unknown (PubMed, Jul 2024).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN E235* TSC2 G440S	endometrial cancer	sensitive	Miransertib	Preclinical - Pdx	Actionable	In a preclinical study, a patient-derived xenograft (PDX) model of endometrial cancer harboring PTEN E235* and TSC2 G440S was sensitive to Miransertib (ARQ092), demonstrating greater than 90% inhibition of tumor growth (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
TSC1 M271T TSC2 L604P	endometrial cancer	sensitive	Miransertib	Preclinical - Pdx	Actionable	In a preclinical study, a patient-derived xenograft (PDX) model of endometrial cancer harboring TSC1 M271T and TSC2 L604P was sensitive to Miransertib (ARQ092), demonstrating greater than 90% inhibition of tumor 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 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 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 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 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
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 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 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 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 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