Reference Detail

Ref Type

Journal Article

PMID

(34337566)

Authors

Portelinha A, Thompson S, Smith RA, Da Silva Ferreira M, Asgari Z, Knezevic A, Seshan V, de Stanchina E, Gupta S, Denis L, Younes A, Reddy S

Title

ASN007 is a selective ERK1/2 inhibitor with preferential activity against RAS-and RAF-mutant tumors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell reports. Medicine	2	7	2021 Jul 20	100350	Cell Rep Med

URL

Abstract Text

Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAFV600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.

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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
ERAS-007	ERAS-007	8	2

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
ERAS-007		ASN007\|ASN-007\|ASN 007\|ERAS007\|ERAS 007	ERK Inhibitor (pan) 21	ERAS-007 (ASN007) is a small molecule that inhibits ERK1/2, which may result in decreased tumor cell proliferation and reduced tumor growth (PMID: 34337566).

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
NRAS G13D	mantle cell lymphoma	sensitive	ERAS-007	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ERAS-007 (ASN007) treatment inhibited proliferation of a mantle cell lymphoma cell line harboring NRAS G13D in culture and inhibited tumor growth in xenograft models (PMID: 34337566).	34337566
NRAS G13D	mantle cell lymphoma	sensitive	Copanlisib + ERAS-007	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination of ERAS-007 (ASN007) and Aliqopa (copanlisib) inhibited tumor growth in a cell line xenograft model of mantle cell lymphoma harboring NRAS G13D, and demonstrated improved efficacy over either agent alone (PMID: 34337566).	34337566
HRAS G12V	urinary bladder cancer	sensitive	ERAS-007	Preclinical - Cell culture	Actionable	In a preclinical study, ERAS-007 (ASN007) treatment inhibited proliferation of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 34337566).	34337566
BRAF V600E	melanoma	sensitive	ERAS-007	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, ERAS-007 (ASN007) treatment inhibited proliferation and Erk signaling in a melanoma cell line harboring BRAF V600E in culture, and inhibited tumor growth in patient-derived xenograft (PDX) models, including a Zelboraf (vemurafenib)-resistant PDX model (PMID: 34337566).	34337566
NRAS Q61K	neuroblastoma	sensitive	ERAS-007	Preclinical - Cell line xenograft	Actionable	In a preclinical study, ERAS-007 (ASN007) treatment inhibited tumor growth in a neuroblastoma cell line xenograft model harboring NRAS Q61K (PMID: 34337566).	34337566
NRAS Q61R	melanoma	sensitive	ERAS-007	Preclinical - Cell culture	Actionable	In a preclinical study, ERAS-007 (ASN007) treatment inhibited proliferation of a melanoma cell line harboring NRAS Q61R in culture (PMID: 34337566).	34337566
BRAF V600E	diffuse large B-cell lymphoma	sensitive	ERAS-007	Preclinical - Cell culture	Actionable	In a preclinical study, ERAS-007 (ASN007) treatment inhibited proliferation of diffuse large B-cell lymphoma cells harboring BRAF V600E in culture (PMID: 34337566).	34337566
NRAS Q61L	liver cancer	sensitive	ERAS-007	Preclinical - Cell culture	Actionable	In a preclinical study, ERAS-007 (ASN007) treatment inhibited proliferation of a liver cancer cell line harboring NRAS Q61L in culture (PMID: 34337566).	34337566
BRAF V600E	colorectal cancer	sensitive	ERAS-007	Preclinical - Pdx & cell culture	Actionable	In a preclinical study, ERAS-007 (ASN007) treatment inhibited cell proliferation and Erk signaling in colorectal cancer cell lines harboring BRAF V600E in culture, and induced tumor regression in two patient-derived xenograft (PDX) models (PMID: 34337566).	34337566