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| Profile Name | NRAS A146T |
| Gene Variant Detail | |
| Relevant Treatment Approaches | MEK inhibitor (Pan) MEK1 Inhibitor MEK2 Inhibitor PI3K Inhibitor (Pan) PIK3CA inhibitor RAS Inhibitor (Pan) |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| NRAS mutant | melanoma | sensitive | Adavosertib | Preclinical | Actionable | In a preclinical study, Adavosertib (MK-1775) showed efficacy in NRAS mutant melanoma and in mutant KRAS colorectal, pancreatic, and lung cancers (PMID: 24791855). | 24791855 |
| NRAS mutant | melanoma | conflicting | 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 mutant | thyroid cancer | sensitive | Selumetinib | Phase I | Actionable | In a Phase I study, selumetinib demonstrated an increase in iodine uptake and retention in a subgroup of patients with thyroid cancer that was refractory to radioiodine; including patients with BRAF and NRAS mutations disease (PMID: 23406027). | 23406027 |
| NRAS mutant | Advanced Solid Tumor | sensitive | Obatoclax | Preclinical | Actionable | In a preclinical study, obatoclax decreased proliferation in human tumor cell lines with NRAS mutation in culture (PMID: 22460902). | 22460902 |
| NRAS mutant | melanoma | sensitive | Binimetinib + Ribociclib | Phase Ib/II | Actionable | In a Phase Ib/II trial, the combination of Binimetinib (MEK162) and Kisqali (ribociclib) resulted in a partial response in 43% (6/14) and stable disease in 43% (6/14) of NRAS mutant melanoma patients (J Clin Oncol 32:5s, 2014 (Suppl;abstr 9009)). | detail... |
| NRAS mutant | melanoma | sensitive | CCT196969 | Preclinical | Actionable | In a preclinical study, CCT196969 inhibited growth of melanoma cells harboring NRAS mutations in culture (PMID: 25500121). | 25500121 |
| NRAS mutant | melanoma | sensitive | CCT241161 | Preclinical | Actionable | In a preclinical study, CCT241161 inhibited growth of melanoma cells harboring NRAS mutations in culture (PMID: 25500121). | 25500121 |
| NRAS mutant | colorectal cancer | no benefit | Cetuximab + Fluorouracil + Irinotecan + Leucovorin | Phase III | Actionable | In a retrospective analysis of a Phase III trial, the combination of Erbitux (cetuximab) and FOLFIRI did not demonstrate an improved clinical benefit compared to FOLFIRI alone in colorectal cancer patients with RAS mutations (PMID: 25605843). | 25605843 |
| NRAS mutant | leukemia | predicted - sensitive | Trametinib | Phase Ib/II | Actionable | In a Phase Ib/II clinical trial, treatment with Mekinist (trametinib) resulted in an overall response rate of 28% in RAS-mutant leukemia patients, with 12% (7/57) of patients achieving complete remission (ASH 2015 Annual Meeting, Abst 677). | detail... |
| NRAS mutant | melanoma | sensitive | BI-69A11 | Preclinical | Actionable | In a preclinical study, BI-69A11 inhibited proliferation and transformation of human melanoma cell lines harboring NRAS mutation in culture (PMID: 26603897). | 26603897 |
| NRAS mutant | melanoma | sensitive | SBI-0640756 | Preclinical | Actionable | In a preclinical study, SBI-0640756 inhibited proliferation and transformation of human melanoma cell lines harboring NRAS mutation in culture (PMID: 26603897). | 26603897 |
| NRAS mutant | melanoma | sensitive | SBI-0640726 | Preclinical | Actionable | In a preclinical study, SBI-0640726 inhibited proliferation and transformation of human melanoma cell lines harboring NRAS mutation in culture (PMID: 26603897). | 26603897 |
| NRAS mutant | melanoma | sensitive | Tubastatin A | Preclinical | Actionable | In a preclinical study, Tubastatin A inhibited proliferation of NRAS mutant melanoma cell lines in culture (PMID: 25957812). | 25957812 |
| NRAS mutant | acute myeloid leukemia | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited proliferation of human NRAS mutant acute myeloid leukemia cell lines in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | melanoma | resistant | Vemurafenib | Preclinical | Actionable | In a preclinical study, human melanoma cell lines harboring a mutation in NRAS were resistant to Zelboraf (vemurafenib) mediated growth inhibition in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | melanoma | sensitive | LY3009120 | Preclinical | Actionable | In a preclinical study, LY3009120 inhibited growth of NRAS mutant human melanoma cell lines in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | autonomic nervous system neoplasm | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human autonomic ganglia cancer cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | acute myeloid leukemia | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human acute myeloid leukemia cell lines harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | lymphoma | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human lymphoma cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | multiple myeloma | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human multiple myeloma cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | non-Hodgkin lymphoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human non-Hodgkin lymphoma cells harboring mutant NRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | central nervous system cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human central nervous system cancer cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | liver cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of liver cancer cell lines harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | lung adenocarcinoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human lung adenocarcinoma cell lines harboring mutant NRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | ovarian cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of ovarian cancer cells harboring mutant NRAS in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | sarcoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human sarcoma cells harboring mutant NRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | transitional cell carcinoma | decreased response | Trametinib | Preclinical | Actionable | In a preclinical study, human urinary tract transitional cell carcinoma cells harboring mutant NRAS were moderately sensitive to Mekinist (trametinib) growth inhibition in culture (PMID: 26343583). | 26343583 |
| NRAS mutant | skin melanoma | sensitive | Binimetinib | Phase III | Actionable | In a Phase III trial, Binimetinib (MEK162) treatment resulted in improved progression free survival (2.8 months), objective response rate (15%, 40/269) and disease control rate (58%, 156/269) compared to Deticene (dacarbazine) (1.5 months, 7%, 25%, respectively) in NRAS-mutant cutaneous melanoma patients (J Clin Oncol 34, 2016 (suppl; abstr 9500)). | detail... |
| NRAS mutant | hematologic cancer | predicted - resistant | SHP099 | Preclinical | Actionable | In a preclinical study, hematopoietic cancer cell lines harboring NRAS mutations demonstrated resistance to SHP099 in cell culture (PMID: 27362227). | 27362227 |
| NRAS mutant | colon cancer | resistant | GDC0879 | Preclinical - Cell culture | Actionable | In a preclinical study, colon cancer cells harboring NRAS mutations were resistant to GDC0879 induced growth inhibition in culture (PMID: 19276360). | 19276360 |
| NRAS mutant | melanoma | no benefit | PD-0325901 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, PD-0325901 treatment resulted in stable tumor growth in melanoma cell line xenograft models harboring an NRAS mutation, however, growth later ensued and thus, demonstrates a lack of benefit (PMID: 27488531). | 27488531 |
| NRAS mutant | melanoma | conflicting | Palbociclib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Ibrance (palbociclib) treatment resulted in stable tumor growth in melanoma cell line xenograft models harboring an NRAS mutation, however, growth later ensued and thus, demonstrated a lack of benefit (PMID: 27488531). | 27488531 |
| NRAS mutant | melanoma | sensitive | Palbociclib + PD-0325901 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination treatment of PD-0325901 and Ibrance (palbociclib) resulted in tumor regression in 33% (2/6) of melanoma xenograft models harboring an NRAS mutation (PMID: 27488531). | 27488531 |
| NRAS mutant | melanoma | sensitive | S63845 + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, combination of S63845 and Mekinist (trametinib) resulted in potent cytotoxic effects in NRAS-mutated melanoma cells in culture compared to the cytostatic effect of Mekinist (trametinib) alone (PMID: 27760111). | 27760111 |
| NRAS mutant | acute myeloid leukemia | predicted - sensitive | AZD5153 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, AZD5153 inhibited proliferation of acute myeloid leukemia cells harboring NRAS mutation in culture, resulted in tumor growth inhibition in cell line xenograft models (PMID: 27573426). | 27573426 |
| NRAS mutant | melanoma | sensitive | Binimetinib + Buparlisib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Binimetinib (MEK162) and Buparlisib (BKM120) resulted in improved cell growth inhibition compared to either agent alone in a metastatic melanoma cell line harboring an NRAS mutation (PMID: 27307593). | 27307593 |
| NRAS mutant | melanoma | sensitive | Buparlisib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Buparlisib (BKM120) treatment in human melanoma cell line xenograft models with brain metastases and harboring an NRAS mutation resulted in inhibition of brain tumor growth and an improved survival benefit (PMID: 27307593). | 27307593 |
| NRAS mutant | melanoma | conflicting | Binimetinib | Phase III | Actionable | In a Phase III clinical trial, treatment with Binimetinib (MEK162) improved median progression-free survival compared to treatment with Deticene (dacarbazine) (2.8 mo. vs. 1.5 mo.), but did not improve overall survival in patients with NRAS-mutant melanoma (PMID: 28284557). | 28284557 |
| NRAS mutant | biliary tract cancer | predicted - sensitive | Binimetinib | Phase I | Actionable | In a Phase I trial, Binimetinib (MEK162) treatment resulted in partial response in a biliary tract cancer patient harboring NRAS mutation (PMID: 28152546) | 28152546 |
| NRAS mutant | melanoma | sensitive | Trametinib | Phase I | Actionable | In a Phase I trial, Mekinist (trametinib) treatment resulted in stable disease in 29% (2/7) of patients with NRAS mutated melanoma (PMID: 22805292; NCT00687622). | 22805292 |
| NRAS mutant | Advanced Solid Tumor | predicted - sensitive | KO-947 | Preclinical - Pdx | Actionable | In a preclinical study, KO-947 resulted in tumor regression in patient derived xenograft (PDX) models harboring either a BRAF mutation, NRAS mutation, or KRAS mutation (EJC Dec 2016, 69:1; S126). | detail... |
| NRAS mutant | Advanced Solid Tumor | no benefit | CC-90003 | Phase I | Actionable | In a Phase Ia trial, CC-90003 treatment did not result in any objective responses and demonstrated toxicity in advanced solid tumor patients harboring KRAS, NRAS, or BRAF mutations (J Clin Oncol 35, 2017 (suppl; abstr 2577)). | detail... |
| NRAS mutant | melanoma | sensitive | Binimetinib + Ribociclib | Phase Ib/II | Actionable | In a Phase Ib trial, the combination of Binimetinib (MEK162) and Kisqali (ribociclib) resulted in a median progression-free survival of 6.7 months, a partial response in 25% (4/16), and stable disease in 44% (7/16) of NRAS mutant melanoma patients (J Clin Oncol 35, 2017 (suppl; abstr 9519)). | detail... |
| NRAS mutant | melanoma | predicted - sensitive | KO-947 | Preclinical - Pdx | Actionable | In a preclinical study, KO-947 inhibited Erk signaling and induced tumor regression in patient-derived xenograft models of NRAS-mutant melanoma (Cancer Res 2017;77(13 Suppl):Abstract nr 5168). | detail... |
| NRAS mutant | pancreatic cancer | predicted - sensitive | KO-947 | Preclinical - Pdx | Actionable | In a preclinical study, KO-947 inhibited Erk signaling and induced tumor regression in patient-derived xenograft models of NRAS-mutant pancreatic cancer (Cancer Res 2017;77(13 Suppl):Abstract nr 5168). | detail... |
| NRAS mutant | colorectal cancer | predicted - sensitive | KO-947 | Preclinical - Pdx | Actionable | In a preclinical study, KO-947 inhibited Erk signaling and induced tumor regression in patient-derived xenograft models of NRAS-mutant colorectal cancer (Cancer Res 2017;77(13 Suppl):Abstract nr 5168). | detail... |
| NRAS mutant | stomach carcinoma | predicted - sensitive | KO-947 | Preclinical - Pdx | Actionable | In a preclinical study, KO-947 inhibited Erk signaling and induced tumor regression in patient-derived xenograft models of NRAS-mutant gastric carcinoma (Cancer Res 2017;77(13 Suppl):Abstract nr 5168). | detail... |
| NRAS mutant | cervix carcinoma | predicted - sensitive | KO-947 | Preclinical - Pdx | Actionable | In a preclinical study, KO-947 inhibited Erk signaling and induced tumor regression in patient-derived xenograft models of NRAS-mutant cervical carcinoma (Cancer Res 2017;77(13 Suppl):Abstract nr 5168). | detail... |
| NRAS mutant | lung non-small cell carcinoma | predicted - sensitive | KO-947 | Preclinical - Pdx | Actionable | In a preclinical study, KO-947 inhibited Erk signaling and induced tumor regression in patient-derived xenograft models of NRAS-mutant non-small cell lung cancer (Cancer Res 2017;77(13 Suppl):Abstract nr 5168). | detail... |
| NRAS mutant | melanoma | predicted - sensitive | Ulixertinib | Case Reports/Case Series | Actionable | In a Phase I trial, treatment with Ulixertinib (BVD-523) resulted in a best response of stable disease in six melanoma patients and a partial response in three melanoma patients all harboring an NRAS mutation (PMID: 29247021; NCT01781429). | 29247021 |
| NRAS exon4 | colon cancer | resistant | Cetuximab | Guideline | Actionable | Erbitux (cetuximab) is not indicated for use in colon cancer patients with NRAS exon 4 mutations (NCCN.org). | detail... |
| NRAS exon4 | colon cancer | resistant | Panitumumab | Guideline | Actionable | Vectibix (panitumumab) is not indicated for use in colon cancer patients with NRAS exon 4 mutations (NCCN.org). | detail... |
| NRAS exon4 | rectum cancer | resistant | Cetuximab | Guideline | Actionable | Erbitux (cetuximab) is not indicated for use in rectum cancer patients with NRAS exon 4 mutations (NCCN.org). | detail... |
| NRAS exon4 | rectum cancer | resistant | Panitumumab | Guideline | Actionable | Vectibix (panitumumab) is not indicated for use in rectum cancer patients with NRAS exon 4 mutations (NCCN.org). | detail... |
| NRAS mutant | colorectal cancer | predicted - resistant | SYM004 | Preclinical - Pdx | Actionable | In a preclinical study, patient-derived xenograft (PDX) models of colorectal cancer harboring KRAS, NRAS or BRAF mutations demonstrated poor response to SYM004 treatment compared to wild-type models (PMID: 29423521). | 29423521 |
| NRAS mutant | Advanced Solid Tumor | sensitive | RAF709 | Preclinical - Cell culture | Actionable | In a preclinical study, cancer cell lines harboring NRAS mutations demonstrated increased sensitivity to RAF709 compared to NRAS wild-type cells in culture (PMID: 29343524). | 29343524 |
| NRAS mutant | neuroblastoma | sensitive | Alpelisib + Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of Alpelisib (BYL719) and Binimetinib (MEK162) led to a synergistic effect in neuroblastoma cells harboring mutant NRAS, demonstrating cell death in culture (PMID: 29437705). | 29437705 |
| NRAS mutant | leukemia | sensitive | Alpelisib + Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of Alpelisib (BYL719) and Binimetinib (MEK162) led to a synergistic effect in leukemia cells harboring mutant NRAS, demonstrating cell death in culture (PMID: 29437705). | 29437705 |
| NRAS mutant | leukemia | sensitive | Belvarafenib | Preclinical - Cell culture | Actionable | In a preclinical study, Belvarafenib (HM95573) inhibited growth of NRAS mutant leukemia cells in culture (Cancer Res 2015;75(15 Suppl):Abstract nr 2607). | detail... |
| NRAS mutant | melanoma | predicted - sensitive | Belvarafenib | Case Reports/Case Series | Actionable | In a Phase I trial, Belvarafenib (HM95573) treatment resulted in an unconfirmed partial response in a patient with NRAS mutant melanoma (Journal of Clinical Oncology 34, no. 15_suppl (May 20 2016) 2570-2570; NCT02405065). | detail... |
| NRAS mutant | hepatocellular carcinoma | sensitive | Refametinib + Sorafenib | Phase II | Actionable | In a Phase II trial, Refametinib (BAY86-9766) and Nexavar (sorafenib) combination treatment resulted in an objective response rate of 6.3% (1/16), a disease control rate of 43.8% (7/16), an overall survival of 12.7 months, and a progression-free survival of 1.5 months in patients unresectable or metastatic hepatocellular carcinoma harboring RAS (NRAS and KRAS) mutations (PMID: 29950351; NCT01915602). | 29950351 |
| NRAS mutant | colorectal cancer | no benefit | Regorafenib | Phase II | Actionable | In a Phase II clinical trial (PREVIUM), Stivarga (regorafenib) treatment resulted in 0% (0/15) 6-month progression free survival (PFS), a 2.2-month median PFS, and a median overall survival of 3.3 months in metastatic colorectal cancer patients with KRAS (n=9), NRAS (n=3) or BRAF (n=2) mutations who failed first line therapy; however, the trial was terminated early due to poor accrual (PMID: 30120161; NCT02175654). | 30120161 |
| NRAS mutant | acute myeloid leukemia | predicted - resistant | Pazopanib | Preclinical - Patient cell culture | Actionable | In a preclinical study, NRAS mutations correlated with resistance to Votrient (pazopanib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). | 30333627 |
| NRAS mutant | acute myeloid leukemia | predicted - resistant | Tivozanib | Preclinical - Patient cell culture | Actionable | In a preclinical study, NRAS mutations correlated with resistance to Fotivda (tivozanib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). | 30333627 |
| NRAS mutant | acute myeloid leukemia | predicted - resistant | Vemurafenib | Preclinical - Patient cell culture | Actionable | In a preclinical study, NRAS mutations correlated with resistance to Zelboraf (vemurafenib) in patient-derived acute myeloid leukemia samples in an ex vivo assay (PMID: 30333627). | 30333627 |
| NRAS mutant | melanoma | sensitive | Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, NRAS-mutant melanoma cell lines were sensitive to treatment with Mekinist (trametinib) in culture, demonstrating decreased cell viability, colony formation, and pathway activity, and increased cell cycle arrest (PMID: 30819666). | 30819666 |
| NRAS mutant | melanoma | conflicting | Palbociclib | Preclinical - Cell culture | Actionable | In a preclinical study, NRAS-mutant melanoma cell lines were sensitive to treatment with Ibrance (palbociclib) in culture, demonstrating decreased cell viability, colony formation, and pathway activity, and increased cell cycle arrest (PMID: 30819666). | 30819666 |
| NRAS mutant | melanoma | predicted - sensitive | Palbociclib + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, melanoma cell lines harboring an NRAS mutation were sensitive to the combination therapy of Ibrance (palbociclib) and Mekinist (trametinib) in culture, demonstrating reduced cell viability, colony formation, and pathway activity, and increased cell cycle arrest (PMID: 30819666). | 30819666 |
| NRAS A146X | colorectal cancer | resistant | Cetuximab | FDA contraindicated | Actionable | Erbitux (cetuximab) treatment of colorectal cancer patients with NRAS exon 4, codon 146 mutations is contraindicated (FDA.gov). | detail... |
| NRAS A146X | colorectal cancer | resistant | Panitumumab | FDA contraindicated | Actionable | Vectibix (panitumumab) treatment of colorectal cancer patients with NRAS exon 4, codon 146 mutations is contraindicated (FDA.gov). | detail... |
| NRAS mutant | melanoma | predicted - sensitive | Belvarafenib | Phase I | Actionable | In Phase I trials, Belvarafenib (HM95573) treatment resulted in partial response in 44% (4/9) of patients with NRAS-mutant melanoma in a dose escalation study, and partial response in 22% (2/9) of NRAS-mutant melanoma patients in a dose expansion study (J Clin Oncol 37, 2019 (suppl; abstr 3000); NCT02405065, NCT03118817). | detail... |
| NRAS mutant | melanoma | predicted - sensitive | Pembrolizumab | Clinical Study - Cohort | Actionable | In a clinical study, NRAS mutations were associated with higher 6-month objective response rate (53.3% vs. 19.6% without NRAS mutations; p=0.019) following treatment with Keytruda (pembrolizumab) or Opdivo (nivolumab) in patients with metastatic melanoma, however, progression-free survival and overall survival were similar between patients with and without NRAS mutations (PMID: 29973670). | 29973670 |
| NRAS mutant | melanoma | predicted - sensitive | Nivolumab | Clinical Study - Cohort | Actionable | In a clinical study, NRAS mutations were associated with higher 6-month objective response rate (53.3% vs. 19.6% without NRAS mutations; p=0.019) following treatment with Keytruda (pembrolizumab) or Opdivo (nivolumab) in patients with metastatic melanoma, however, progression-free survival and overall survival were similar between patients with and without NRAS mutations (PMID: 29973670). | 29973670 |
| NRAS mutant | skin melanoma | sensitive | Binimetinib | Guideline | Actionable | Mektovi (binimetinib) is included in guidelines as second-line therapy for patients with metastatic or unresectable cutaneous melanoma harboring an NRAS mutation (NCCN.org). | detail... |
| NRAS mutant | Advanced Solid Tumor | no benefit | LY3009120 | Case Reports/Case Series | Actionable | In a Phase I trial, LY3009120 did not achieve expected pharmacodynamic effects, resulted in stable disease as best overall response in 1 of 5 patients with advanced or metastatic cancer harboring NRAS mutations (PMID: 31645440; NCT02014116). | 31645440 |
| NRAS act mut | lung non-small cell carcinoma | predicted - resistant | Osimertinib | Case Reports/Case Series | Actionable | In a retrospective analysis, activating NRAS mutations were identified in 1 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416). | 31839416 |
| NRAS mutant | melanoma | predicted - sensitive | Cobimetinib + UNC2025 | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of UNC2025 and Cotellic (cobimetinib) resulted in greater inhibition of colony formation and apoptotic induction in melanoma cells harboring an NRAS mutation in culture when compared to either therapy alone (PMID: 30482852). | 30482852 |
| NRAS mutant | differentiated high-grade thyroid carcinoma | predicted - sensitive | Pazopanib + Trametinib | Phase I | Actionable | In a Phase I trial, of 10 differentiated thyroid cancer patients, 3 of 3 responders (all partial responses) to treatment with the combination of Votrient (pazopanib) and Mekinist (trametinib) harbored NRAS mutations, while none of the seven patients with stable disease or progressive disease had NRAS mutations (PMID: 31186313; NCT01438554). | 31186313 |
| NRAS mutant | 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 an NRAS mutation (PMID: 30833748). | 30833748 |
| NRAS mutant | Erdheim-Chester disease | sensitive | Cobimetinib | Guideline | Actionable | Cotellic (cobimetinib) is included in guidelines as preferred first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring mutations in the MAPK pathway such as ARAF, NRAS, KRAS, MAP2K1/2, PIK3CA, or with no detectable mutations, or for whom testing is not available (NCCN.org). | detail... |
| NRAS mutant | Erdheim-Chester disease | sensitive | Trametinib | Guideline | Actionable | Mekinist (trametinib) is included in guidelines as first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring mutations in the MAPK pathway such as ARAF, NRAS, KRAS, MAP2K1/2, PIK3CA, or with no detectable mutations, or for whom testing is not available (NCCN.org). | detail... |
| NRAS mutant | myelofibrosis | not applicable | N/A | Guideline | Prognostic | NRAS mutations are associated with decreased overall survival in patients with primary myelofibrosis (NCCN.org). | detail... |
| NRAS mutant | melanoma | predicted - sensitive | Belvarafenib + Cobimetinib | Phase I | Actionable | In a Phase I trial, Belvarafenib (HM95573) and Cotellic (cobimetinib) combination therapy was tolerable, and resulted in a response rate of 38% (5/13, 5 partial response) in patients with melanoma harboring NRAS mutations, with a median progression-free survival of 7.3 months (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 3007-3007; NCT03284502). | detail... |
| NRAS act mut | Advanced Solid Tumor | no benefit | Selumetinib | Clinical Study - Cohort | Actionable | In a Phase II trial (Pediatric MATCH), Koselugo (selumetinib) treatment was tolerated but did not result in an objective response in pediatric patients with advanced solid tumors including high-grade glioma (n=8) and rhabdomyosarcoma (n=7) harboring MAPK pathway alterations including BRAF V600E (n=2), activating KRAS (n=8)/HRAS (n=1)/NRAS (n=3) or inactivating NF1 (n=7) mutations, with a 6-month progression-free survival of 15% (3/20) and 3 stable disease as best response (PMID: 35363510; NCT03213691). | 35363510 |
| NRAS mutant | medullary thyroid carcinoma | sensitive | Cabozantinib | Guideline | Actionable | Cometriq (cabozantinib) is included in guidelines for patients with advanced or metastatic medullary thyroid carcinoma harboring RAS mutations (PMID: 31549998, PMID: 35491008; ESMO.org). | 35491008 31549998 detail... |
| NRAS mutant | medullary thyroid carcinoma | sensitive | Cabozantinib | Phase III | Actionable | In a Phase III trial, Cometriq (cabozantinib) treatment resulted in improved progression-free survival (47 vs 8 weeks, HR 0.15, p=0.0317) compared to placebo in thyroid medullary carcinoma patients harboring RAS mutations (PMID: 27525386). | 27525386 |
| NRAS act mut | melanoma | predicted - sensitive | Binimetinib + Ribociclib | Phase Ib/II | Actionable | In a Phase Ib/II trial, Kisqali (ribociclib) plus Mektovi (binimetinib) was well tolerated in NRAS-mutant melanoma patients and resulted in an overall response rate of 19.5% (8/41; all PR), disease control rate of 70.7% (29/41), median duration of response of 10.3mo, median progression-free survival of 3.7mo, and median overall survival of 11.3mo in phase II, and a response rate of 22.9% (16/70) in patients with an NRAS Q61 mutation, and 12.5% (1/8) with NRAS G12/G13 mutation (PMID: 35294522; NCT01781572). | 35294522 |
| NRAS act mut | melanoma | predicted - sensitive | Binimetinib + Exarafenib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Exarafenib (KIN-2787) and Mektovi (binimetinib) combination treatment inhibited growth of melanoma cell lines harboring NRAS mutations in culture, and resulted in improved tumor growth inhibition and Mapk pathway suppression in cell line xenograft models compared to either agent alone (J Clin Oncol 40, 2022 (suppl 16; abstr e15099)). | detail... |
| NRAS mutant | melanoma | predicted - sensitive | LXH 254 + Trametinib | Phase I | Actionable | In a Phase Ib trial, treatment with the combination of LXH 254 and Mekinist (trametinib) demonstrated safety and resulted in an overall response rate of 30% (9/30, all partial responses), a disease control rate of 73.3% (22/30), with stable disease in 13 patients, and a median progression-free survival of 5.03 months in patients with melanoma harboring NRAS mutations (PMID: 36947734; NCT02974725). | 36947734 |
| NRAS mutant | Advanced Solid Tumor | predicted - sensitive | FCN-159 | Preclinical - Pdx | Actionable | In a preclinical study, FCN-159 inhibited tumor growth in patient-derived xenograft (PDX) models harboring NRAS mutations (Cancer Res 2020;80(16 Suppl):Abstract nr 1951). | detail... |
| NRAS mutant | melanoma | predicted - sensitive | LTT462 + LXH 254 | Phase II | Actionable | In a Phase II trial, combination treatment with LXH 254 and LTT462 demonstrated tolerable safety in patients with NRAS-mutant melanoma, and led to a disease control rate of 62% (18/29), with a confirmed partial response in 6 patients and stable disease in 12 patients (Ann Oncol (2022) 33 (suppl_7): S197-S224; NCT04417621). | detail... |
| NRAS act mut | melanoma | predicted - sensitive | FCN-159 | Phase I | Actionable | In a Phase I trial (FCN-159-001), FCN-159 treatment was well tolerated in melanoma patients harboring NRAS activating mutations and resulted in an objective response rate (ORR) of 19% (4/21, all partial responses), a clinical benefit rate (CBR) of 52.4% (11/21), and a median progression-free survival (mPFS) of 3.8 mo across all doses tested, and a CBR of 50% (3/6), mPFS of 3.8 mo at the RP2D dose of 12mg (PMID: 36113242; NCT03932253). | 36113242 |
| NRAS act mut | multiple myeloma | predicted - sensitive | BMF-219 | Preclinical - Cell culture | Actionable | In a preclinical study, BMF-219 inhibited growth of multiple myeloma cell lines harboring NRAS activating mutations in culture (Cancer Res 2022;82(12_Suppl):Abstract nr 2654). | detail... |
| NRAS act mut | melanoma | predicted - sensitive | Tunlametinib | Phase I | Actionable | In a Phase I trial, Tunlametinib (HL-085) treatment demonstrated acceptable tolerability and resulted in an objective response rate (ORR) of 14.3% (6/42; all partial responses), a disease control rate (DCR) of 78.6%, and a median progression-free survival (PFS) of 3.0 months in patients with advanced melanoma harboring NRAS mutations, and an ORR of 26.7% (4/15), a DCR of 86.7%, and median PFS of 3.6 months at the recommended Phase II dose (PMID: 36600247; NCT03973151). | 36600247 |
| NRAS act mut | neuroblastoma | predicted - sensitive | Navitoclax + Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to Navitoclax (ABT-263), resulting in reduced cell viability in culture, and the combination treatment resulted in tumor regression in cell line xenograft models (6/6 partial responses) (PMID: 36895472). | 36895472 |
| NRAS act mut | neuroblastoma | predicted - sensitive | Trametinib + Venetoclax | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to Venclexta (venetoclax), resulting in reduced cell viability in culture, and the combination treatment resulted in tumor growth inhibition with 2/6 partial responses and 3/6 with stable disease in cell line xenograft models (PMID: 36895472). | 36895472 |
| NRAS act mut | neuroblastoma | predicted - sensitive | S63845 + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an NRAS activating mutation to S63845 (MIK655), resulting in reduced cell viability in culture (PMID: 36895472). | 36895472 |
| NRAS exon4 | colorectal cancer | resistant | Panitumumab | Guideline | Actionable | Vectibix (panitumumab) is not indicated for use in metastatic colorectal cancer patients with NRAS exon 4 mutations (PMID: 36307056; ESMO.org). | 36307056 detail... |
| NRAS exon4 | colorectal cancer | resistant | Cetuximab | Guideline | Actionable | Erbitux (cetuximab) is not indicated for use in metastatic colorectal cancer patients with NRAS exon 4 mutations (PMID: 36307056; ESMO.org). | 36307056 detail... |
| NRAS act mut | melanoma | predicted - sensitive | Exarafenib | Case Reports/Case Series | Actionable | In a Phase I trial, Exarafenib (KIN-2787) was tolerated and resulted in a partial response in 17.6% (6/34) and stable disease in 23.5% (8/34) of patients with BRAF-driven advanced solid tumors or NRAS-driven melanoma, including a partial response in 1 melanoma patient harboring an NRAS mutation (Cancer Res (2023) 83 (8_Supplement): CT032; NCT04913285). | detail... |
| NRAS act mut | melanoma | decreased response | Toripalimab-tpzi | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Loqtorz (toripalimab-tpzi) resulted in a median disease-free survival of 9 months in melanoma patients harboring activating NRAS mutations in either G12 (29%) or Q61 (67.1%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p<0.0001) (PMID: 37403699). | 37403699 |
| NRAS act mut | melanoma | decreased response | Pembrolizumab | Clinical Study | Actionable | In a retrospective analysis, real-world treatment with either Keytruda (pembrolizumab) or Toripalimab (JS001) resulted in a median disease-free survival of 9 months in melanoma patients harboring activating NRAS mutations in either G12 (29%) or Q61 (67.1%) compared to 32 months in patients with wild-type BRAF, NRAS, and KIT (p<0.0001) (PMID: 37403699). | 37403699 |
| NRAS mutant | female reproductive organ cancer | sensitive | Navitoclax + Trametinib | Phase Ib/II | 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, with a median duration of response of 8.17 months, a median progression-free survival of 4.8 months, and a median overall survival of 18.13 months (PMID: 38456660; NCT02079740). | 38456660 |
| NRAS mutant | Advanced Solid Tumor | predicted - sensitive | IK-595 | Preclinical | Actionable | In a preclinical study, IK-595 inhibited Mek and Erk phosphorylation and decreased tumor growth in an NRAS-mutant mouse tumor model (Mol Cancer Res (2023) 21 (5_Supplement): PR10). | detail... |
| NRAS act mut | melanoma | predicted - sensitive | Tunlametinib | Phase II | Actionable | In a Phase II trial, Tunlametinib (HL-085) treatment demonstrated safety and activity in Chinese patients with advanced melanoma harboring NRAS mutations (including mutations at Q61, G12, and G13), with an 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 (PMID: 38479118; NCT05217303). | 38479118 |
| NRAS act mut | melanoma | sensitive | BAY 11-7082 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, BAY 11-7082 induced apoptosis and decreased Akt signaling, viability, and colony formation in melanoma cell lines harboring activating NRAS mutations in culture and inhibited tumor growth in a cell line xenograft model (PMID: 38982514). | 38982514 |
| NRAS act mut | melanoma | predicted - sensitive | Binimetinib + Exarafenib | Case Reports/Case Series | Actionable | In a Phase I trial, treatment with the combination of Exarafenib (KIN-2787) and Mektovi (binimetinib) demonstrated safety in patients with NRAS-mutant melanoma (n=39) or other advanced solid tumors driven by BRAF class I or II alterations (n=10 and n=3) and resulted in a partial response in 35.5% (11/31, 9 confirmed partial responses) of efficacy evaluable NRAS-mutant melanoma patients (Ann Oncol (2024) 35 (Suppl_2): S491-S492; NCT04913285). | detail... |