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| Gene | NRAS |
| Variant | Q61K |
| Impact List | missense |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | NRAS Q61K is a hotspot mutation that lies within a GTP-binding region of the Nras protein (UniProt.org). Q61K results in activation of downstream pathway signaling, increased survival, and transformation of cultured cells (PMID: 22718121, PMID: 34117033, PMID: 33431353), and is predicted to lead to a loss of Nras protein function based on the effects of HRAS Q61K (PMID: 3510078). |
| Associated Drug Resistance | |
| Category Variants Paths |
NRAS mutant NRAS exon3 NRAS Q61X NRAS Q61K NRAS mutant NRAS act mut NRAS Q61K |
| Transcript | NM_002524.5 |
| gDNA | chr1:g.114713909G>T |
| cDNA | c.181C>A |
| Protein | p.Q61K |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_002524 | chr1:g.114713909G>T | c.181C>A | p.Q61K | RefSeq | GRCh38/hg38 |
| NM_002524.4 | chr1:g.114713909G>T | c.181C>A | p.Q61K | RefSeq | GRCh38/hg38 |
| NM_002524.5 | chr1:g.114713909G>T | c.181C>A | p.Q61K | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| NRAS Q61K | lung non-small cell carcinoma | decreased response | Gedatolisib | Preclinical | Actionable | In a preclinical study, human non-small cell lung cancer cells harboring NRAS Q61K had a decreased response to Gedatolisib (PKI-587) in culture (PMID: 21325073, PMID: 12068308). | 21325073 12068308 |
| NRAS Q61K | melanoma | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited soft agar growth of human melanoma cancer cells harboring NRAS Q61K in culture (PMID: 26343583). | 26343583 |
| NRAS Q61K | melanoma | sensitive | Selumetinib | Preclinical | Actionable | In a preclinical study, Selumetinib (AZD6244) inhibited proliferation of human melanoma cell lines harboring NRAS Q61K in culture (PMID: 26343583). | 26343583 |
| NRAS Q61K | melanoma | resistant | Vemurafenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a cell line xenograft model of melanoma harboring NRAS Q61K demonstrated resistance to Zelboraf (vemurafenib) treatment (PMID: 30559419). | 30559419 |
| NRAS Q61K | melanoma | resistant | Vemurafenib | Preclinical | Actionable | In a preclinical study, human melanoma cell lines harboring NRAS Q61K were insensitive to Zelboraf (vemurafenib) in culture (PMID: 26343583). | 26343583 |
| NRAS Q61K | lung non-small cell carcinoma | sensitive | Pimasertib | Preclinical - Cell culture | Actionable | In a preclinical study, Pimasertib (MSC1936369B) inhibited proliferation of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 23629727). | 23629727 |
| NRAS Q61K | lung non-small cell carcinoma | sensitive | Everolimus + Pimasertib | Preclinical - Cell culture | Actionable | In a preclinical study, Pimasertib (MSC1936369B) and Afinitor (everolimus) synergistically inhibited proliferation of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 23629727). | 23629727 |
| NRAS Q61K | lung non-small cell carcinoma | sensitive | Pimasertib + Sorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Pimasertib (MSC1936369B) and Nexavar (sorafenib) synergistically inhibited proliferation of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 23629727). | 23629727 |
| NRAS Q61K | lung non-small cell carcinoma | sensitive | Pimasertib + Regorafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Pimasertib (MSC1936369B) and Stivarga (regorafenib) synergistically inhibited proliferation of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 23629727). | 23629727 |
| NRAS Q61K | 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 Q61K | melanoma | predicted - sensitive | RAF709 | Preclinical - Cell culture | Actionable | In a preclinical study, RAF709 inhibited Erk signaling in melanoma cells harboring NRAS Q61K in culture (PMID: 29343524). | 29343524 |
| NRAS Q61K | lung cancer | sensitive | RAF709 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, RAF709 inhibited Erk signaling and proliferation of lung cancer cells harboring NRAS Q61K in culture, and resulted in tumor regression in cell line xenograft models (PMID: 29343524). | 29343524 |
| 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 | 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 | 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 | 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 | 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 | 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 | 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 | melanoma | sensitive | Chelidonine | Preclinical - Cell culture | 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 Q61K in culture (PMID: 32156748). | 32156748 |
| NRAS Q61K | melanoma | predicted - sensitive | UCM-1336 | Preclinical - Cell culture | Actionable | In a preclinical study, UCM-1336 treatment inhibited growth of melanoma cells harboring NRAS Q61K in culture (PMID: 31181882). | 31181882 |
| NRAS Q61K | acute myeloid leukemia | predicted - sensitive | UCM-1336 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, UCM-1336 treatment inhibited growth of acute myeloid leukemia cells harboring NRAS Q61K in culture, and reduced bone marrow tumor burden and significantly prolonged survival (HR=6.211; p=0.0274) in cell line xenograft models (PMID: 31181882). | 31181882 |
| NRAS Q61K | melanoma | resistant | PLX8394 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, PLX8394 treatment did not inhibit Erk signaling or reduce tumor growth in a Zelboraf (vemurafenib)-resistant cell line xenograft model of melanoma harboring NRAS Q61K (PMID: 30559419). | 30559419 |
| NRAS Q61K | lung non-small cell carcinoma | predicted - resistant | BI-3406 | Preclinical - Cell culture | Actionable | In a preclinical study, BI-3406 treatment failed to inhibit growth of non-small cell lung cancer cells harboring NRAS Q61K in culture (PMID: 32816843). | 32816843 |
| NRAS Q61K | neuroblastoma | not predictive | Rigosertib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Rigosertib (ON01910) inhibited cell viability and induced apoptosis and cell cycle arrest in neuroblastoma cells harboring NRAS Q61K in culture, and delayed tumor growth in cell line xenograft models, however, cells with wild-type NRAS demonstrated the same response, and mechanistically, the response was found to be due to Rigosertib (ON0190) binding to tubulin (PMID: 33158997). | 33158997 |
| NRAS Q61K | uveal melanoma | no benefit | YM-254890 | Preclinical - Cell culture | Actionable | In a preclinical study, transformed mouse melanocytes expressing NRAS Q61K were insensitive to treatment with YM-254890 (PMID: 33229459). | 33229459 |
| NRAS Q61K | 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 Q61K 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 Q61K | melanoma | decreased response | Lifirafenib + Vemurafenib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination treatment of Lifirafenib (BGB-283) and Zelboraf (vemurafenib) in Mekinist (trametinib)-resistant melanoma cells harboring NRAS Q61K 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 Q61K | melanoma | no benefit | Lifirafenib + Ulixertinib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Ulixertinib (BVD-523) to Lifirafenib (BGB-283) treatment did not lead to inhibition of cell growth when compared to the combination treatment of Lifirafenib (BGB-283) and Mekinist (trametinib) in MEK inhibitor resistant melanoma cells harboring NRAS Q61K in culture (PMID: 33318037). | 33318037 |
| NRAS Q61K | melanoma | no benefit | Lifirafenib + MK-8353 | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of MK-8353 to Lifirafenib (BGB-283) treatment did not lead to inhibition of cell growth when compared to the combination treatment of Lifirafenib (BGB-283) and Mekinist (trametinib) in MEK inhibitor resistant melanoma cells harboring NRAS Q61K in culture (PMID: 33318037). | 33318037 |
| NRAS Q61K | 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 Q61K (PMID: 33318037). | 33318037 |
| NRAS Q61K | colorectal cancer | predicted - sensitive | Binimetinib | Case Reports/Case Series | Actionable | In a Phase II trial (MATCH), Mektovi (binimetinib) treatment resulted in stable disease in two patient with colorectal cancer harboring NRAS Q61K, whom remained on treatment for 12 and 17 months until disease progression (PMID: 33637626; NCT02465060). | 33637626 |
| NRAS Q61K | melanoma | predicted - sensitive | Belvarafenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Belvarafenib (HM95573) treatment led to inhibition of tumor growth in a melanoma cell line xenograft model harboring NRAS Q61K (PMID: 33953400). | 33953400 |
| 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 Q61K | lung carcinoma | sensitive | LY3214996 | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, patient-derived lung carcinoma cells harboring NRAS Q61K were sensitive to LY3214996 treatment in culture, and LY3214996 treatment led to reduction of tumor growth in a patient-derived xenograft (PDX) model (PMID: 33536188). | 33536188 |
| NRAS Q61K | lung carcinoma | sensitive | Abemaciclib + LY3214996 | Preclinical - Pdx | Actionable | In a preclinical study, combination treatment with LY3214996 and Verzenio (abemaciclib) led to additive effects on tumor growth inhibition in a patient-derived xenograft (PDX) model of lung carcinoma harboring NRAS Q61K (PMID: 33536188). | 33536188 |
| NRAS Q61K | melanoma | sensitive | ASTX029 | Preclinical - Pdx | Actionable | In a preclinical study, ASTX029 treatment inhibited growth of melanoma cell lines harboring NRAS Q61K in culture, and inhibited tumor growth in a patient-derived xenograft (PDX) model of melanoma harboring NRAS Q61K (PMID: 34330842). | 34330842 |
| NRAS Q61K | lung non-small cell carcinoma | sensitive | Lifirafenib + PD-0325901 | Phase I | Actionable | In a Phase Ib trial, Lifirafenib (BGB-283) and PD-0325901 combination treatment demonstrated safety and activity in patients with advanced solid tumors harboring MAPK pathway alterations, resulting in an objective response rate of 27.8% (15/54, 1 complete and 14 partial responses), including an objective response in a patient with non-small cell lung cancer harboring NRAS Q61K (Cancer Res (2023) 83 (8_Supplement): CT033). | detail... |
| NRAS Q61K | lung non-small cell carcinoma | sensitive | Lifirafenib + PD-0325901 | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Lifirafenib (BGB-283) and PD-0325901 synergistically inhibited proliferation of a non-small cell lung cancer cell line harboring NRAS Q61K in culture, and demonstrated improved efficacy over either agent alone (PMID: 32336014). | 32336014 |
| NRAS Q61K | lung non-small cell carcinoma | sensitive | Lifirafenib + Pimasertib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Lifirafenib (BGB-283) and Pimasertib (MSC1936369B) synergistically inhibited proliferation of a non-small cell lung cancer cell line harboring NRAS Q61K in culture, and demonstrated improved efficacy over either agent alone (PMID: 32336014). | 32336014 |
| NRAS Q61K | thyroid cancer | predicted - sensitive | Everolimus + RO5126766 | Case Reports/Case Series | Actionable | In a Phase I trial, the combination of Afinitor (everolimus) and RO5126766 (VS-6766) resulted in a partial response in a patient with thyroid cancer harboring NRAS Q61K (Journal of Clinical Oncology 2022 40:16_suppl, 9018-9018; NCT02407509). | detail... |
| NRAS Q61K | colorectal cancer | sensitive | Palbociclib + Trametinib | Preclinical - Pdx | Actionable | In a preclinical study, combination treatment with Ibrance (palbociclib) and Mekinist (trametinib) led to greater inhibition of tumor growth than either agent alone in a patient-derived xenograft (PDX) model of colorectal cancer harboring NRAS Q61K (PMID: 35913398). | 35913398 |
| NRAS Q61K | melanoma | sensitive | Binimetinib + Ribociclib | Preclinical - Cell culture | Actionable | In a preclinical study, combination treatment with Mektovi (binimetinib) and Kisqali (ribociclib) resulted in greater inhibition cell growth compared to either agent alone in a melanoma cell line harboring NRAS Q61K in culture (PMID: 29496665). | 29496665 |
| NRAS Q61K | colon cancer | resistant | Cetuximab | Preclinical - Cell culture | Actionable | In a preclinical study, a colon cancer cell line expressing NRAS Q61K was resistant to Erbitux (cetuximab) in culture (PMID: 27636997). | 27636997 |
| NRAS Q61K | colon cancer | sensitive | Cetuximab + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Erbitux (cetuximab) and Mekinist (trametinib) synergistically induced apoptosis and inhibited viability of a colon cancer cell line expressing NRAS Q61K in culture (PMID: 27636997). | 27636997 |
| NRAS Q61K | colon cancer | sensitive | Cetuximab + Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Erbitux (cetuximab) and Koselugo (selumetinib) synergistically induced apoptosis and inhibited viability of a colon cancer cell line expressing NRAS Q61K in culture (PMID: 27636997). | 27636997 |
| NRAS Q61K | colon cancer | sensitive | Cetuximab + Pimasertib | Preclinical - Cell culture | Actionable | In a preclinical study, Erbitux (cetuximab) and Pimasertib (MSC19363669B) synergistically induced apoptosis and inhibited proliferation and viability of a colon cancer cell line expressing NRAS Q61K in culture (PMID: 27636997). | 27636997 |
| NRAS Q61K | neuroblastoma | sensitive | BI-1347 + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of BI-1347 to Mekinist (trametinib) resulted in enhanced growth inhibition of a neuroblastoma cell line harboring NRAS Q61K compared to Mekinist (trametinib) alone in culture (PMID: 36398965). | 36398965 |
| NRAS Q61K | neuroblastoma | sensitive | BI-1347 + Selumetinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of BI-1347 and Koselugo (selumetinib) resulted in reduced tumor growth and improved survival compared to Koselugo (selumetinib) alone in a neuroblastoma cell line xenograft model harboring NRAS Q61K (PMID: 36398965). | 36398965 |
| NRAS Q61K | melanoma | predicted - sensitive | BGB3245 | Case Reports/Case Series | Actionable | In a Phase I trial, BGB3245 treatment demonstrated manageable safety and resulted in a disease control rate of 48% (16/33,1 complete response, 5 confirmed partial responses (PR), 2 unconfirmed PR, and 8 stable disease > 24 weeks) in patients with advanced solid tumors harboring MAPK pathway alterations, including a partial response in a patient with melanoma harboring NRAS Q61K (Cancer Res (2023) 83 (8_Supplement): CT031). | detail... |
| NRAS Q61K | neuroblastoma | sensitive | 4SC-205 + Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of 4SC-205 and Koselugo (selumetinib) inhibited viability to a greater degree than either therapy alone in a neuroblastoma cell line harboring NRAS Q61K (PMID: 34709738). | 34709738 |
| NRAS Q61K | 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 34.7%, a median progression-free survival of 4.2 months, and 1-year survival rate of 57.2% in patients with advanced melanoma harboring NRAS mutations including NRAS Q61R (40%), Q61K (29.5%), and G12D (9.5%) (J Clin Oncol 41, 2023 (suppl 16; abstr 9510); NCT05217303). | detail... |
| NRAS Q61K | thyroid cancer | sensitive | IHMT-RAF-128 | Preclinical - Cell culture | Actionable | In a preclinical study, IHMT-RAF-128 inhibited proliferation in a thyroid cancer cell line harboring NRAS Q61K in culture (PMID: 37164118). | 37164118 |