Reference Detail

Ref Type

Journal Article

PMID

(31744895)

Authors

Bhagwat SV, McMillen WT, Cai S, Zhao B, Whitesell M, Shen W, Kindler L, Flack RS, Wu W, Anderson B, Zhai Y, Yuan XJ, Pogue M, Van Horn RD, Rao X, McCann D, Dropsey AJ, Manro J, Walgren J, Yuen E, Rodriguez MJ, Plowman GD, Tiu RV, Joseph S, Peng SB

Title

ERK Inhibitor LY3214996 Targets ERK Pathway-Driven Cancers: A Therapeutic Approach Toward Precision Medicine.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	19	2	2020 02	325-336	Mol Cancer Ther

URL

Abstract Text

The ERK pathway is critical in oncogenesis; aberrations in components of this pathway are common in approximately 30% of human cancers. ERK1/2 (ERK) regulates cell proliferation, differentiation, and survival and is the terminal node of the pathway. BRAF- and MEK-targeted therapies are effective in BRAF V600E/K metastatic melanoma and lung cancers; however, responses are short-lived due to emergence of resistance. Reactivation of ERK signaling is central to the mechanisms of acquired resistance. Therefore, ERK inhibition provides an opportunity to overcome resistance and leads to improved efficacy. In addition, KRAS-mutant cancers remain an unmet medical need in which ERK inhibitors may provide treatment options alone or in combination with other agents. Here, we report identification and activity of LY3214996, a potent, selective, ATP-competitive ERK inhibitor. LY3214996 treatment inhibited the pharmacodynamic biomarker, phospho-p90RSK1, in cells and tumors, and correlated with LY3214996 exposures and antitumor activities. In in vitro cell proliferation assays, sensitivity to LY3214996 correlated with ERK pathway aberrations. LY3214996 showed dose-dependent tumor growth inhibition and regression in xenograft models harboring ERK pathway alterations. Importantly, more than 50% target inhibition for up to 8 to 16 hours was sufficient for significant tumor growth inhibition as single agent in BRAF- and KRAS-mutant models. LY3214996 also exhibited synergistic combination benefit with a pan-RAF inhibitor in a KRAS-mutant colorectal cancer xenograft model. Furthermore, LY3214996 demonstrated antitumor activity in BRAF-mutant models with acquired resistance in vitro and in vivo. Based on these preclinical data, LY3214996 has advanced to an ongoing phase I clinical trial (NCT02857270).

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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
LY3214996	LY3214996	11	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
LY3214996		Temuterkib\|LY-3214996\|LY 3214996	ERK Inhibitor (pan) 21	LY3214996 inhibits ERK1/2, potentially resulting in decreased growth of tumors with alterations in the RAS/MAPK pathway (AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4973, PMID: 31744895).

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 Q61L	melanoma	predicted - sensitive	LY3214996	Preclinical - Cell culture	Actionable	In a preclinical study, a melanoma cell line harboring NRAS Q61L was sensitive to treatment with LY3214996 in culture, demonstrating decreased cell proliferation (PMID: 31744895).	31744895
BRAF T119S BRAF V600E	colorectal cancer	predicted - sensitive	LY3214996	Preclinical - Cell culture	Actionable	In a preclinical study, a colorectal cancer cell line harboring BRAF V600E and BRAF T119S was sensitive to treatment with LY3214996 in culture, demonstrating decreased cell proliferation (PMID: 31744895).	31744895
BRAF V600E	colorectal cancer	predicted - sensitive	LY3214996	Preclinical - Cell culture	Actionable	In a preclinical study, a lung cancer cell line harboring BRAF V600E and NF1 T2805I was sensitive to treatment with LY3214996 in culture, demonstrating decreased cell viability (PMID: 31744895).	31744895
BRAF V600E	melanoma	sensitive	LY3214996	Preclinical - Cell line xenograft	Actionable	In a preclinical study, LY3214996 treatment in a melanoma cell line harboring BRAF V600E led to decreased cell proliferation in culture, and inhibition of tumor growth in a cell line xenograft model (PMID: 31744895).	31744895
MAP2K1 Q56P MAP2K1 H119Y MAP2K1 D351G	colorectal cancer	predicted - sensitive	LY3214996	Preclinical - Cell line xenograft	Actionable	In a preclinical study, LY3214996 treatment in a colorectal cancer cell line harboring MAP2K1 Q56P, MAP2K1 H119Y, and MAP2K1 D351G led to decreased cell proliferation in culture, and inhibition of tumor growth in a cell line xenograft model (PMID: 31744895).	31744895
MAP2K1 Q56P	lung cancer	predicted - sensitive	LY3214996	Preclinical - Cell culture	Actionable	In a preclinical study, a lung cancer cell line harboring MAP2K1 Q56P was sensitive to treatment with LY3214996 in culture, demonstrating decreased cell proliferation (PMID: 31744895).	31744895