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|Ref Type||Journal Article|
|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.|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|II-B08||SHP2 Inhibitor 19||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 + 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||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|
|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 + 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||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||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|