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| Gene | NRAS |
| Variant | Q61R |
| Impact List | missense |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | NRAS Q61R is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). Q61R results in increased GTP-bound Nras, which leads to activation of Mapk signaling and cell transformation in culture (PMID: 16818621, PMID: 34117033), and is predicted to lead to a loss of GTPase activity based on the effect of HRAS Q61R (PMID: 3510078). |
| Associated Drug Resistance | |
| Category Variants Paths |
NRAS mutant NRAS act mut NRAS Q61R NRAS mutant NRAS exon3 NRAS Q61X NRAS Q61R |
| Transcript | NM_002524.5 |
| gDNA | chr1:g.114713908T>C |
| cDNA | c.182A>G |
| Protein | p.Q61R |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_002524.5 | chr1:g.114713908T>C | c.182A>G | p.Q61R | RefSeq | GRCh38/hg38 |
| NM_002524 | chr1:g.114713908T>C | c.182A>G | p.Q61R | RefSeq | GRCh38/hg38 |
| NM_002524.4 | chr1:g.114713908T>C | c.182A>G | p.Q61R | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| NRAS Q61R | acral lentiginous melanoma | sensitive | Trametinib | Preclinical - Patient cell culture | Actionable | In a preclinical study, Mekinist (trametinib) treatment inhibited viability of patient-derived acral melanoma cells harboring NRAS Q61R in culture (PMID: 39001563). | 39001563 |
| NRAS Q61R | acute biphenotypic leukemia | no benefit | Trametinib | Case Reports/Case Series | Actionable | In a clinical study, Mekinist (trametinib) treatment was well tolerated and led to an initial decrease of peripheral blasts in a pediatric patient with mixed phenotype acute leukemia harboring NRAS Q61R who had previously undergone a stem cell transplant, but patient experienced progressive disease after 2 months, and died soon after (PMID: 33563661; NCT02670525). | 33563661 |
| NRAS Q61R | urinary bladder cancer | sensitive | Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Mekinist (trametinib) treatment decreased tumor weight of a cell line xenograft model of bladder cancer harboring NRAS Q61R (PMID: 34554931). | 34554931 |
| NRAS Q61R | gastrointestinal neuroendocrine tumor | sensitive | Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Mekinist (trametinib) inhibited viability, proliferation, and migration of a cell line derived from a pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) model harboring NRAS Q61R in culture and inhibited tumor growth and increased survival compared to treatment with vehicle in a patient-derived xenograft (PDX) cell line model (PMID: 38959709). | 38959709 |
| NRAS Q61R | ameloblastoma | sensitive | GDC-0623 | Preclinical - Cell culture | Actionable | In a preclinical study, GDC-0623 inhibited Erk phosphorylation and viability of an ameloblastoma cell line harboring NRAS Q61R in culture (PMID: 35689405). | 35689405 |
| NRAS Q61R | melanoma | sensitive | Binimetinib | Phase II | Actionable | In a Phase II trial, Binimetinib (MEK162) treatment resulted in partial response in 20% (6/30), and stable disease in 43% (13/30) of melanoma patients harboring NRAS mutations, including Q61L (1/30), Q61K (9/30), and Q61R (15/30) (PMID: 23414587). | 23414587 |
| NRAS Q61R | colorectal cancer | predicted - sensitive | Binimetinib | Case Reports/Case Series | Actionable | In a Phase II trial (MATCH), Mektovi (binimetinib) treatment resulted in an unconfirmed partial response in a patient with colorectal cancer harboring NRAS Q61R, with a 48.2% tumor reduction at cycle 4, but the disease progressed at cycle 7 (PMID: 33637626; NCT02465060). | 33637626 |
| NRAS Q61R | ameloblastoma | predicted - sensitive | Binimetinib | Case Reports/Case Series | Actionable | In a Phase II trial (MATCH), Mektovi (binimetinib) treatment resulted in a partial response in a patient with metastatic malignant ameloblastoma harboring NRAS Q61R, and the patient stayed on treatment for 26 months (PMID: 33637626; NCT02465060). | 33637626 |
| NRAS Q61R | thyroid cancer | sensitive | MK2206 | Preclinical - Cell culture | Actionable | In a preclinical study, MK2206 inhibited AKT activation, proliferation, and growth of thyroid cancer cell lines with PI3K/AKT pathway alterations in culture, including an anaplastic thyroid cancer cell line harboring NRAS Q61R (PMID: 21289267). | 21289267 |
| NRAS Q61R | melanoma | sensitive | PD-0325901 | Preclinical - Cell culture | Actionable | In a preclinical study, PD-0325901 treatment induced cell cycle arrest and inhibited growth of melanoma cells harboring NRAS Q61R in culture (PMID: 25422890). | 25422890 |
| NRAS Q61R | urinary bladder cancer | sensitive | RAF265 | Preclinical - Cell culture | Actionable | In a preclinical study, RAF265 treatment decreased viability of a bladder cancer cell line harboring NRAS Q61R in culture (PMID: 34554931). | 34554931 |
| NRAS Q61R | melanoma | resistant | PLX8394 | Preclinical - Cell culture | Actionable | In a preclinical study, melanoma cells harboring NRAS Q61R demonstrated resistance to PLX8394 treatment in culture (PMID: 30559419). | 30559419 |
| NRAS Q61R | ovarian cancer | predicted - sensitive | Navitoclax + Trametinib | Case Reports/Case Series | Actionable | In a Phase I/II trial, treatment with the combination of Navitoclax (ABT-263) and Mekinist (trametinib) resulted in a partial response rate of 33.3% (7/21) amongst efficacy evaluable patients with gynecologic cancers harboring mutations in KRAS or NRAS, including a partial response in a patient with ovarian cancer harboring NRAS Q61R (PMID: 38456660; NCT02079740). | 38456660 |
| NRAS Q61R | melanoma | sensitive | RO5126766 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, RO5126766 (VS-6766) treatment induced cell cycle arrest, decreased Mek and Erk phosphorylation, and inhibited growth of melanoma cells harboring NRAS Q61R in culture, and inhibited tumor growth in cell line xenograft models (PMID: 25422890). | 25422890 |
| NRAS Q61R | melanoma | predicted - sensitive | LY3009120 | Preclinical - Cell culture | Actionable | In a preclinical study, LY3009120 treatment inhibited Erk activation and reduced proliferation of melanoma cells harboring NRAS Q61R and wild-type RAF in culture (PMID: 30559419). | 30559419 |
| NRAS Q61R | melanoma | predicted - sensitive | TAK-632 | Preclinical - Cell culture | Actionable | In a preclinical study, TAK-632 treatment inhibited Erk activation and reduced proliferation of melanoma cells harboring NRAS Q61R and wild-type RAF in culture, but at a higher concentration than was required to inhibit melanoma cells harboring BRAF V600E (PMID: 30559419). | 30559419 |
| NRAS Q61R | urinary bladder cancer | sensitive | LXH 254 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, LXH 254 treatment decreased Mek signaling, colony formation and viability, and increased apoptosis in a bladder cancer cell line harboring NRAS Q61R in culture and decreased tumor weight and volume in a cell line xenograft model (PMID: 34554931). | 34554931 |
| NRAS Q61R | melanoma | predicted - sensitive | BGB659 | Preclinical - Cell culture | Actionable | In a preclinical study, BGB659 treatment inhibited Erk activation and reduced proliferation of melanoma cells harboring NRAS Q61R and wild-type RAF in culture (PMID: 30559419). | 30559419 |
| NRAS Q61R | melanoma | sensitive | ASTX029 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, ASTX029 treatment inhibited growth of melanoma cell lines harboring NRAS Q61R in culture, and inhibited tumor growth in cell line xenograft models (PMID: 34330842). | 34330842 |
| NRAS Q61R | melanoma | predicted - sensitive | Belvarafenib | Case Reports/Case Series | Actionable | In a Phase I trial, Belvarafenib (HM95573) treatment in a melanoma patient harboring NRAS Q61R led to a tumor reduction of 84% after 24 weeks of treatment and a confirmed partial response at 12 weeks, and response to treatment was maintained for 40 weeks (PMID: 33953400; NCT03118817). | 33953400 |
| NRAS Q61R | Advanced Solid Tumor | sensitive | Belvarafenib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing NRAS Q61R were sensitive to treatment with Belvarafenib (HM95573) in culture, demonstrating decreased cell viability (PMID: 33953400). | 33953400 |
| 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 |
| NRAS Q61R | urinary bladder cancer | sensitive | LXH 254 + Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, LXH 254 and Mekinist (trametinib) combination treatment decreased tumor volume and weight compared to vehicle in a cell line xenograft model of bladder cancer harboring NRAS Q61R (PMID: 34554931). | 34554931 |
| NRAS Q61R | melanoma | predicted - sensitive | Tunlametinib | Case Reports/Case Series | Actionable | In a Phase I trial, Tunlametinib (HL-085) treatment demonstrated safety and preliminary efficacy in patients with advanced melanoma harboring NRAS mutations, resulting in an objective response rate of 37.5% (3/8), a disease control rate of 75% (6/8), and a median progression-free survival of 114.0 days in patients harboring NRAS Q61R at the recommended Phase II dose (PMID: 36600247; NCT03973151). | 36600247 |
| NRAS Q61R | melanoma | predicted - sensitive | Tunlametinib | Case Reports/Case Series | Actionable | In a Phase II trial, Tunlametinib (HL-085) treatment resulted in a confirmed objective response rate of 35.8% (34/95, all partial responses), a median progression-free survival of 4.2 months, disease control rate of 72.6% (69/95), median duration of response of 6.1 months, and median overall survival of 13.7 months in Chinese patients with advanced melanoma harboring NRAS mutations including NRAS Q61R (40%), Q61K (29.5%), and G12D (9.5%) (PMID: 38479118; NCT05217303). | 38479118 |
| NRAS Q61R | melanoma | sensitive | Chelidonine | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Chelidonine treatment inhibited activation of Nras and downstream signaling pathways, reduced proliferation and colony formation, and induced apoptosis in melanoma cells harboring NRAS Q61R in culture, and inhibited tumor growth and increased survival in a cell line xenograft model (PMID: 32156748). | 32156748 |
| NRAS Q61R | melanoma | sensitive | Chloroquine + Trametinib | Preclinical - Pdx | Actionable | In a preclinical study, combination treatment with Mekinist (trametinib) and Chloroquine resulted in tumor regression in a melanoma patient-derived xenograft (PDX) model harboring NRAS Q61R (PMID: 30833748). | 30833748 |
| NRAS Q61R | melanoma | sensitive | Lifirafenib + Trametinib | Preclinical - Pdx | Actionable | In a preclinical study, the combination treatment of Mekinist (trametinib) and Lifirafenib (BGB-283) resulted in durable tumor regression compared to stabilized tumor growth when treated with either agent alone in patient-derived xenograft (PDX) models of melanoma harboring NRAS Q61R (PMID: 33318037). | 33318037 |
| NRAS Q61R | melanoma | decreased response | Lifirafenib + SCH772984 | Preclinical - Cell culture | Actionable | In a preclinical study, the combination treatment of Lifirafenib (BGB-283) and SCH772984 in Mekinist (trametinib)-resistant melanoma cells harboring NRAS Q61R in culture resulted in a decreased response compared to the combination treatment with Lifirafenib (BGB-283) and Mekinist (trametinib), demonstrating reduced inhibition of cell growth (PMID: 33318037). | 33318037 |
| NRAS Q61R | melanoma | sensitive | Binimetinib + RAF709 | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Mektovi (binimetinib) and RAF709 resulted in inhibition of cell growth in a MEK inhibitor-resistant melanoma cell line harboring NRAS Q61R (PMID: 33318037). | 33318037 |
| NRAS Q61R | urinary bladder cancer | sensitive | RAF265 + Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, RAF265 and Mekinist (trametinib) combination treatment decreased Erk1/2 phosphorylation in cultured cells and decreased tumor volume and weight of a cell line xenograft model harboring NRAS Q61R (PMID: 34554931). | 34554931 |
| NRAS Q61R | melanoma | predicted - sensitive | IMM-1-104 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, IMM-1-104 treatment led to tumor growth regression in a cell line xenograft model of melanoma harboring NRAS Q61R (Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P252). | detail... |
| NRAS Q61R | melanoma | predicted - sensitive | PHI-501 | Preclinical - Cell culture | Actionable | In a preclinical study, PHI-501 inhibited growth and migration and induced apoptosis in a melanoma cell line harboring NRAS Q61R in culture (Cancer Res (2023) 83 (7_Supplement): 1627). | detail... |
| NRAS Q61R | melanoma | sensitive | NST-628 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, NST-628 inhibited viability of a melanoma cancer cell line harboring NRAS Q61R in culture and induced tumor regression in an intracranial cell line xenograft model (PMID: 38588399). | 38588399 |