Reference Detail

Ref Type

Journal Article

PMID

(32586982)

Authors

Valencia-Sama I, Ladumor Y, Kee L, Adderley T, Christopher G, Robinson CM, Kano Y, Ohh M, Irwin MS

Title

NRAS Status Determines Sensitivity to SHP2 Inhibitor Combination Therapies Targeting the RAS-MAPK Pathway in Neuroblastoma.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	80	16	2020 Aug 15	3413-3423	Cancer Res

URL

Abstract Text

Survival for high-risk neuroblastoma remains poor and treatment for relapsed disease rarely leads to long-term cures. Large sequencing studies of neuroblastoma tumors from diagnosis have not identified common targetable driver mutations other than the 10% of tumors that harbor mutations in the anaplastic lymphoma kinase (ALK) gene. However, at neuroblastoma recurrence, more frequent mutations in genes in the RAS-MAPK pathway have been detected. The PTPN11-encoded tyrosine phosphatase SHP2 is an activator of the RAS pathway, and we and others have shown that pharmacologic inhibition of SHP2 suppresses the growth of various tumor types harboring KRAS mutations such as pancreatic and lung cancers. Here we report inhibition of growth and downstream RAS-MAPK signaling in neuroblastoma cells in response to treatment with the SHP2 inhibitors SHP099, II-B08, and RMC-4550. However, neuroblastoma cell lines harboring endogenous NRASQ61K mutation (which is commonly detected at relapse) or isogenic neuroblastoma cells engineered to overexpress NRASQ61K were distinctly resistant to SHP2 inhibitors. Combinations of SHP2 inhibitors with other RAS pathway inhibitors such as trametinib, vemurafenib, and ulixertinib were synergistic and reversed resistance to SHP2 inhibition in neuroblastoma in vitro and in vivo. These results suggest for the first time that combination therapies targeting SHP2 and other components of the RAS-MAPK pathway may be effective against conventional therapy-resistant relapsed neuroblastoma, including those that have acquired NRAS mutations. SIGNIFICANCE: These findings suggest that conventional therapy-resistant, relapsed neuroblastoma may be effectively treated via combined inhibition of SHP2 and MEK or ERK of the RAS-MAPK pathway.

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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
II-B08	II-B08	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
II-B08			SHP2 Inhibitor 20	II-B08 is an inhibitor of Shp2, which may result in inhibition of Erk1/2 and decrease cell proliferation (PMID: 20170098, PMID: 32586982).

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 Q61K	neuroblastoma	sensitive	SHP099 + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination treatment of SHP099 and Zelboraf (vemurafenib) in neuroblastoma cell lines either expressing or harboring NRAS Q61K resulted in increased sensitivity compared to Zelboraf (vemurafenib) treatment alone in culture, demonstrating a greater decrease in cell viability (PMID: 32586982).	32586982
NRAS Q61K	neuroblastoma	sensitive	SHP099 + Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination treatment of SHP099 and Mekinist (trametinib) resulted in a synergistic effect in neuroblastoma cell lines either harboring or expressing NRAS Q61K, demonstrating greater cell growth inhibition compared to either agent alone in culture and delayed tumor growth, increased apoptotic activity, and improved survival in cell line xenograft models (PMID: 32586982).	32586982
NRAS Q61K	neuroblastoma	predicted - resistant	SHP099	Preclinical - Cell line xenograft	Actionable	In a preclinical study, neuroblastoma cell lines either harboring or expressing NRAS Q61K demonstrated resistance to treatment with SHP099, with increased cell viability and proliferation compared to wild-type Nras in culture, and moderate growth inhibition in cell line xenograft models compared when compared to combination therapies (PMID: 32586982).	32586982
NRAS Q61K	neuroblastoma	predicted - sensitive	Ulixertinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, neuroblastoma cell lines either harboring or expressing NRAS Q61K demonstrated moderate growth inhibition in culture when treated with Ulixertinib (BVD-523) (PMID: 32586982).	32586982
NRAS Q61K	neuroblastoma	predicted - sensitive	Trametinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, neuroblastoma cell lines either harboring or expressing NRAS Q61K demonstrated moderate growth inhibition in culture and in cell line xenograft models when treated with Mekinist (trametinib) (PMID: 32586982).	32586982
NRAS Q61K	neuroblastoma	sensitive	SHP099 + Ulixertinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, the combination treatment of SHP099 and Ulixertinib (BVD-523) resulted in a synergistic effect in neuroblastoma cell line xenograft models harboring NRAS Q61K, demonstrating a greater delay in tumor growth when compared to either agent alone (PMID: 32586982).	32586982
NRAS Q61K	neuroblastoma	no benefit	Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, neuroblastoma cells with NRAS Q61K showed minimal response to treatment with Zelboraf (vemurafenib) in culture (PMID: 32586982).	32586982