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| Gene Symbol | HRAS | ||||||||||
| Synonyms | C-BAS/HAS | C-H-RAS | C-HA-RAS1 | CTLO | H-RASIDX | HAMSV | HRAS1 | p21ras | RASH1 | ||||||||||
| Gene Description | HRAS, HRas proto-oncogene, GTPase, is a member of the small GTPase family that upon activation by growth factors stimulates multiple downstream pathways such as RAF and PI3K to promote cell proliferation and survival (PMID: 21779504, PMID: 32241873). HRAS activating mutations are commonly found in tumors, including dermatological, head and neck, thyroid, kidney, bladder cancers (PMID: 29524560), squamous cell papilloma (PMID: 31960612), and breast adenomyoepitheliomas (PMID: 31887226). | ||||||||||
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| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| HRAS wild-type | melanoma | sensitive | E6201 | Preclinical | Actionable | In a preclinical study, E6201 inhibited proliferation of several melanoma cell lines in culture and hypersensitivity was associated with wild-type HRAS (PMID: 23039341). | 23039341 |
| HRAS wild-type | cancer | predicted - sensitive | FTI-277 | Preclinical | Actionable | In a preclinical study, the farnesyltransferase inhibitor FTI-277 sensitized Hras transformed rat fibroblasts to radiation therapy (PMID: 8620483). | 8620483 |
| HRAS mutant | endometrial cancer | sensitive | Trametinib | Preclinical | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of human endometrial cancer cells harboring mutant HRAS in culture (PMID: 26343583). | 26343583 |
| HRAS mutant | transitional cell carcinoma | resistant | Trametinib | Preclinical | Actionable | In a preclinical study, human urinary transitional cell carcinoma cells harboring mutant HRAS were insensitive to Mekinist (trametinib) in culture (PMID: 26343583). | 26343583 |
| HRAS mutant | Advanced Solid Tumor | predicted - sensitive | Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, human solid tumor cell lines harboring HRAS mutations demonstrated increased sensitivity to growth inhibition by Afinitor (everolimus) in culture compared to cell lines with wild-type HRAS (PMID: 26544513). | 26544513 |
| HRAS mutant | Advanced Solid Tumor | predicted - sensitive | Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Binimetinib (MEK162) inhibited growth and induced apoptosis in human solid tumor cell lines harboring HRAS mutations in culture (PMID: 26544513). | 26544513 |
| HRAS mutant | Advanced Solid Tumor | predicted - sensitive | Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, human solid tumor cell lines harboring HRAS mutations demonstrated increased sensitivity to growth inhibition by Selumetinib (AZD6244) in culture compared to cell lines with wild-type HRAS (PMID: 26544513). | 26544513 |
| HRAS mutant | transitional cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS missense (Q61R, G12S, G13R) or frameshift (V29Cfs*19) mutations, progression-free survival was significantly improved in patients harboring HRAS mutations (5.1 vs 0.8 months, HR=0.262) compared to wild-type patients (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS mutant | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial (AIM-HN), Zarnestra (tipifarnib) demonstrated safety and preliminary activity in patients with recurrent or metastatic head and neck squamous cell carcinoma harboring mutations in HRAS, resulting in an objective response rate of 20% (10/50, 1 complete and 9 partial responses), disease control rate of 48% (24/50), with stable disease in 14 patients, median progression-free survival of 2.6 mo, and median overall survival of 7 mo (Ann Oncol (2023) 34 (suppl_2): S1286-S1287; NCT03719690). | detail... |
| HRAS mutant | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial (KO-TIP-001), Zarnestra (tipifarnib) treatment resulted in an objective response rate of 55% (11/20) in patients with head and neck squamous cell carcinoma harboring HRAS missense mutations at a variant allele frequency over 20%, with nine patients achieved stable disease and a median progression-free survival of 5.6 months (PMID: 33750196; NCT02383927). | 33750196 |
| HRAS mutant | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, head and neck squamous cell carcinoma cell lines harboring an HRAS mutation were sensitive to treatment with Zarnestra (tipifarnib), demonstrating reduced cell growth and decreased phosphorylation of Erk and Mek, and inhibition of spheroid viability in culture (PMID: 32727882). | 32727882 |
| HRAS mutant | salivary gland cancer | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial (KO-TIP-001), Zarnestra (tipifarnib) treatment resulted in an objective response rate of 8% (1/12) in patients with recurrent or metastatic salivary gland cancer harboring HRAS mutations, with a median progression-free survival of 7 months (J Clin Oncol 38: 2020 (suppl; abstr 6504); NCT02383927). | detail... |
| HRAS mutant | thyroid gland medullary 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... |
| HRAS mutant | thyroid gland medullary 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 |
| HRAS mutant | urinary bladder cancer | sensitive | Metformin | Preclinical | Actionable | In a preclinical study, mouse models of bladder cancer harboring an HRAS mutation were sensitive to Glucophage (metformin), resulting in tumor growth reduction and prevention of hyperplasia regression (PMID: 26921394). | 26921394 |
| HRAS mutant | ovarian cancer | predicted - sensitive | Alpelisib + Binimetinib | Phase Ib/II | Actionable | In a Phase Ib study, Alpelisib (BYL719) in combination with Binimetinib (MEK162) demonstrated preliminary safety and efficacy in patients with RAS-mutant advanced solid tumors, including patients with ovarian cancer (J Clin Oncol 32:5s, 2014 (suppl; abstr 9051). | detail... |
| HRAS mutant | breast cancer | decreased response | PI-273 | Preclinical - Cell culture | Actionable | In a preclinical study, breast cancer cell lines harboring RAS mutations, including HRAS-mutant cell lines, demonstrated decreased sensitivity to growth inhibition by PI-273, in culture (PMID: 28827373). | 28827373 |
| HRAS mut PIK3CA R88Q | high grade glioma | sensitive | Buparlisib + Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in growth inhibition of astrocytoma cells with an HRAS mutation and expressing PIK3CA R88Q in culture, but at a higher drug concentration compared to cells without mutant HRAS (PMID: 29975751). | 29975751 |
| HRAS mut PIK3CA E542K | high grade glioma | sensitive | Buparlisib + Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in growth inhibition of astrocytoma cells with an HRAS mutation expressing PIK3CA E542K in culture, but at a higher drug concentration compared to cells without mutant HRAS (PMID: 29975751). | 29975751 |
| HRAS mut PIK3CA M1043V | high grade glioma | sensitive | Buparlisib + Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination therapy of Buparlisib (BKM120) and Koselugo (selumetinib) led to a synergistic effect, resulting in growth inhibition of astrocytoma cells with an HRAS mutation and expressing PIK3CA M1043V in culture, but at a higher drug concentration compared to cells without mutant HRAS (PMID: 29975751). | 29975751 |
| HRAS Q61K | rhabdomyosarcoma | no benefit | Trametinib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, Mekinist (trametinib) inhibited ERK signaling and viability in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture, but did not inhibit ERK signaling in cell line xenograft models and led to tumor progression (PMID: 34737198). | 34737198 |
| HRAS Q61K | rhabdomyosarcoma | not predictive | Rigosertib | Preclinical - Cell culture | Actionable | In a preclinical study, Rigosertib (ON01910) inhibited cell viability and induced apoptosis and cell cycle arrest in rhabdomyosarcoma cells harboring HRAS Q61K in culture, however, cells with wild-type HRAS demonstrated the same response, and mechanistically, the response was found to be due to Rigosertib (ON0190) binding to tubulin (PMID: 33158997). | 33158997 |
| HRAS Q61K | rhabdomyosarcoma | sensitive | LY3009120 + LY3214996 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, LY3214996 and LY3009120 combination treatment synergistically induced cell cycle arrest and apoptosis in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture and induced tumor growth regression in a xenograft model (PMID: 34737198). | 34737198 |
| HRAS Q61K | rhabdomyosarcoma | sensitive | LY3009120 + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Mekinist (trametinib) and LY3009120 combination treatment synergistically inhibited Erk phosphorylation, proliferation, and colony formation and induced cell cycle arrest and apoptosis in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture (PMID: 34737198). | 34737198 |
| HRAS Q61K | rhabdomyosarcoma | sensitive | LY3214996 + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Mekinist (trametinib) and LY3214996 combination treatment synergistically inhibited growth and induced apoptosis and cell cycle arrest in rhabdomyosarcoma cell lines harboring HRAS Q61K in culture and induced tumor regression in a xenograft model (PMID: 34737198). | 34737198 |
| HRAS Q61K | rhabdomyosarcoma | sensitive | Ganitumab + Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Mekinist (trametinib) and Ganitumab (AMG-479) synergistically inhibited growth of rhabdomyosarcoma cell lines harboring HRAS Q61K in culture, and resulted in tumor regression and increased survival compared to either treatment alone in a cell line xenograft model (PMID: 36322002). | 36322002 |
| BRAF G466E HRAS Q61K | melanoma | sensitive | Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Mekinist (trametinib) reduced ERK signaling and inhibited proliferation of a melanoma cell line harboring BRAF G466E and HRAS Q61K in culture (PMID: 28783719). | 28783719 |
| HRAS Q61K PTEN dec exp | rhabdomyosarcoma | resistant | Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, decreasing Pten expression through shRNA knockdown in a rhabdomyosarcoma cell line harboring HRAS Q61K conferred resistance to Mekinist (trametinib) treatment in culture (PMID: 36322002). | 36322002 |
| HRAS Q61K PTEN dec exp | rhabdomyosarcoma | sensitive | Ganitumab + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Ganitumab (AMG-479) sensitized a rhabdomyosarcoma cell line harboring HRAS Q61K with low PTEN expression to treatment with Mekinist (trametinib), resulting in reduced cell growth in culture (PMID: 36322002). | 36322002 |
| HRAS G12S | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a clinical case study, Zarnestra (tipifarnib) treatment resulted in a partial response that lasted for 8 months in a patient with ear canal squamous cell carcinoma harboring HRAS G12S (PMID: 38219706). | 38219706 |
| HRAS G12S | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS G12S was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). | 32727882 |
| HRAS G12S | renal pelvis transitional cell carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS mutations, a patient with renal pelvis transitional cell carcinoma harboring HRAS G12S achieved a partial response (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS G12S | head and neck squamous cell carcinoma | sensitive | Alpelisib + Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, treatment with the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) resulted in enhanced tumor growth inhibition compared to monotherapy in a patient-derived xenograft (PDX) model of head and neck squamous cell carcinoma harboring HRAS G12S (PMID: 38219706). | 38219706 |
| HRAS G12V | Advanced Solid Tumor | resistant | Cetuximab | Preclinical | Actionable | In a preclinical study, tumor cells expressing HRAS G12V demonstrated resistance to treatment with Erbitux (cetuximab) (PMID: 22797062). | 22797062 |
| HRAS G12V | melanoma | sensitive | CI-1040 | Preclinical | Actionable | In a preclinical study CI-1040 (PD-184352) inhibited melanoma progression in a transgenic zebrafish model of melanoma expressing HRAS G12V (PMID: 26267534). | 26267534 |
| HRAS G12V | Advanced Solid Tumor | sensitive | Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing HRAS G12V demonstrated sensitivity to growth inhibition by Afinitor (everolimus) in culture (PMID: 26544513). | 26544513 |
| HRAS G12V | Advanced Solid Tumor | sensitive | Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing HRAS G12V demonstrated sensitivity to growth inhibition by Binimetinib (MEK162) in culture (PMID: 26544513). | 26544513 |
| HRAS G12V | Advanced Solid Tumor | resistant | Panitumumab | Preclinical | Actionable | In a preclinical study, tumor cells expressing HRAS G12V demonstrated resistance to treatment with Vectibix (panitumumab) (PMID: 22797062). | 22797062 |
| HRAS G12V | urinary bladder cancer | sensitive | RAF265 | Preclinical - Cell culture | Actionable | In a preclinical study, RAF265 treatment decreased viability and colony formation of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 34554931). | 34554931 |
| HRAS G12V | high grade glioma | sensitive | SF1126 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, SF1126 inhibited Akt activation, proliferation, and migration of transgenic mouse glioma cells expressing HRAS G12V in culture, and suppressed tumor growth in xenograft models (PMID: 25425962). | 25425962 |
| HRAS G12V | head and neck squamous cell carcinoma | sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, Zarnestra (tipifarnib) treatment led to decreased cell viability and inhibition of clonogenic and anchorage-independent growth in a head and neck squamous cell carcinoma cell line harboring HRAS G12V in culture (PMID: 35247914). | 35247914 |
| HRAS G12V | Advanced Solid Tumor | sensitive | Rigosertib Sodium | Preclinical - Cell culture | Actionable | In a preclinical study, Rigosertib (ON 01910.Na) inhibited oncogenic transformation in fibroblast cells over-expressing HRAS G12V in culture (PMID: 27104980). | 27104980 |
| HRAS G12V | Advanced Solid Tumor | sensitive | Pz-1 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Pz-1 reduced tumor growth in xenograft models of transformed cells over expressing HRAS G12V in a dose-dependent manner (PMID: 26126987). | 26126987 |
| HRAS G12V | urinary bladder cancer | sensitive | LXH 254 | Preclinical - Cell culture | Actionable | In a preclinical study, LXH 254 treatment decreased viability of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 34554931). | 34554931 |
| HRAS G12V | urinary bladder cancer | sensitive | Everolimus + Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Selumetinib (AZD6244) and Afinitor (everolimus) reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 26544513). | 26544513 |
| HRAS G12V | urinary bladder cancer | sensitive | Binimetinib + Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a bladder cell line harboring HRAS G12V in culture (PMID: 26544513). | 26544513 |
| HRAS G12V | Advanced Solid Tumor | sensitive | Binimetinib + Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) worked synergistically to inhibit growth of transformed cells expressing HRAS G12V in culture (PMID: 26544513). | 26544513 |
| HRAS G12V | Advanced Solid Tumor | predicted - sensitive | SR9009 | Preclinical - Cell culture | Actionable | In a preclinical study, SR9009 treatment resulted in apoptosis in HRAS G12V-induced senescent firbroblast cells in culture (PMID: 29320480). | 29320480 |
| HRAS G12V | Advanced Solid Tumor | predicted - sensitive | SR9011 | Preclinical - Cell culture | Actionable | In a preclinical study, SR9011 treatment resulted in apoptosis in HRAS G12V-induced senescent firbroblast cells in culture (PMID: 29320480). | 29320480 |
| HRAS G12V | urinary bladder cancer | sensitive | ERAS-007 | Preclinical - Cell culture | Actionable | In a preclinical study, ERAS-007 (ASN007) treatment inhibited proliferation of a bladder cancer cell line harboring HRAS G12V in culture (PMID: 34337566). | 34337566 |
| HRAS G12V | Advanced Solid Tumor | sensitive | WM-8014 | Preclinical | Actionable | In a preclinical study, WM-8014 inhibited proliferation of a transformed mouse cell line expressing HRAS G12V in culture, and inhibited proliferation and induced senescence in a transgenic zebrafish model (PMID: 30069049). | 30069049 |
| HRAS G12V | head and neck squamous cell carcinoma | predicted - sensitive | Alpelisib + Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Piqray (alpelisib) sensitized head and neck squamous cell carcinoma cell lines harboring HRAS G12V to treatment with Zarnestra (tipifarnib), resulting in enhanced growth inhibition and apoptosis in culture (PMID: 35247914). | 35247914 |
| HRAS G12V | urinary bladder cancer | sensitive | RAF265 + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, RAF265 and Mekinist (trametinib) combination treatment inhibited colony formation compared to RAF265 alone in cultured cells harboring HRAS G12V (PMID: 34554931). | 34554931 |
| FGFR3 dec exp FGFR3 wild-type HRAS G12V | transitional cell carcinoma | resistant | AZD4547 | Preclinical | Actionable | In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to AZD4547 in culture (PMID: 22869148). | 22869148 |
| FGFR3 dec exp FGFR3 wild-type HRAS G12V | transitional cell carcinoma | resistant | PD173074 | Preclinical | Actionable | In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to PD173074 in culture (PMID: 22869148). | 22869148 |
| FGFR3 dec exp FGFR3 wild-type HRAS G12V | transitional cell carcinoma | decreased response | AZ8010 | Preclinical | Actionable | In a preclinical study, urothelial cancer cells with low expression of wild-type FGFR3 that harbored HRAS G12V demonstrated resistance to AZ8010 in culture (PMID: 22869148). | 22869148 |
| HRAS G12V HRAS R135A | Advanced Solid Tumor | resistant | NS1 | Preclinical | Actionable | In a preclinical study, introducing HRAS R135A mutation in transformed cells expressing HRAS G12V resulted in reduced binding of Hras to NS1, leading to resistance to Mapk pathway inhibition in cell culture (PMID: 27820802). | 27820802 |
| HRAS G12V HRAS R135K | Advanced Solid Tumor | resistant | NS1 | Preclinical | Actionable | In a preclinical study, introducing HRAS R135K mutation in transformed cells expressing HRAS G12V resulted in reduced binding of Hras to NS1, leading to resistance to Mapk pathway inhibition in cell culture (PMID: 27820802). | 27820802 |
| HRAS inact mut | thyroid cancer | sensitive | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 inhibited growth of thyroid cancer cells harboring an HRAS pathway activating mutation in cell culture (PMID: 21831957). | 21831957 |
| HRAS A59T RET A883F RET A883T | thyroid gland medullary carcinoma | predicted - resistant | Pralsetinib | Case Reports/Case Series | Actionable | In a retrospective analysis, a medullary thyroid carcinoma patient harboring RET A883T progressed on treatment with Gavreto (pralsetinib) and was found to have acquired RET A883F and HRAS A59T (PMID: 38127829; NCT03157128, NCT03037385, NCT03780517). | 38127829 |
| HRAS G12C | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a head and neck squamous cell carcinoma cell line xenograft model harboring HRAS G12C was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth and vessel formation, increased apoptotic activity, and decreased cell proliferation (PMID: 32727882). | 32727882 |
| HRAS G12C | Advanced Solid Tumor | sensitive | Sotorasib | Preclinical - Cell culture | Actionable | In a preclinical study, Lumakras (sotorasib) inhibited viability of cultured cells expressing HRAS G12C (PMID: 38236605). | 38236605 |
| HRAS G12C | Advanced Solid Tumor | sensitive | JDQ443 | Preclinical - Cell culture | Actionable | In a preclinical study, JDQ443 inhibited viability of cultured cells expressing HRAS G12C (PMID: 38236605). | 38236605 |
| HRAS G12C | Advanced Solid Tumor | sensitive | RM-018 | Preclinical - Cell culture | Actionable | In a preclinical study, RM-018 inhibited viability of cultured cells expressing HRAS G12C (PMID: 38236605). | 38236605 |
| HRAS G12D | head and neck squamous cell carcinoma | sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, Zarnestra (tipifarnib) treatment led to decreased cell viability and inhibition of clonogenic and anchorage-independent growth in head and neck squamous cell carcinoma cell lines harboring HRAS G12D in culture (PMID: 35247914). | 35247914 |
| HRAS G12D | head and neck squamous cell carcinoma | sensitive | Alpelisib + Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Piqray (alpelisib) sensitized head and neck squamous cell carcinoma cell lines harboring HRAS G12D to treatment with Zarnestra (tipifarnib), resulting in enhanced growth inhibition and increased apoptosis in culture (PMID: 35247914). | 35247914 |
| HRAS G12D | Advanced Solid Tumor | no benefit | MRTX-1133 | Preclinical - Cell culture | Actionable | In a preclinical study, cultured cells expressing HRAS G12D were not sensitive to treatment with MRTX1133 (PMID: 37339170). | 37339170 |
| HRAS G12D | head and neck squamous cell carcinoma | sensitive | SCH772984 + Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of SCH772984 sensitized head and neck squamous cell carcinoma cell lines harboring HRAS G12D to treatment with Zarnestra (tipifarnib), resulting in enhanced growth inhibition and increased apoptosis in culture (PMID: 35247914). | 35247914 |
| HRAS G12D | head and neck squamous cell carcinoma | sensitive | Tipifarnib + Ulixertinib | Preclinical - Cell culture | Actionable | In a preclinical study, combination treatment with Ulixertinib (BVD-523) and Zarnestra (tipifarnib) resulted in a synergistic effect, with enhanced apoptosis in a head and neck squamous cell carcinoma cell lines harboring HRAS G12D in culture (PMID: 35247914). | 35247914 |
| HRAS G12D HRAS Q95H | Advanced Solid Tumor | sensitive | MRTX-1133 | Preclinical - Cell culture | Actionable | In a preclinical study, cultured cells expressing HRAS G12D and HRAS Q95H were sensitive to treatment with MRTX1133, demonstrating decreased cell viability (PMID: 37339170). | 37339170 |
| HRAS G13R | thyroid cancer | sensitive | Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Mekinist (trametinib) inhibited growth of a thyroid cancer cell line harboring HRAS G13R in culture (PMID: 27222538). | 27222538 |
| HRAS G13R | 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 HRAS G13R (PMID: 21289267). | 21289267 |
| HRAS G13R | thyroid cancer | sensitive | Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Selumetinib (AZD6244) inhibited growth of a thyroid cancer cell line harboring HRAS G13R in culture (PMID: 27222538). | 27222538 |
| HRAS G13R | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS G13R was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). | 32727882 |
| HRAS G13R | renal pelvis transitional cell carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS mutations, a patient with renal pelvis transitional cell carcinoma harboring HRAS G13R achieved a partial response (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS G13R | thyroid cancer | sensitive | Dasatinib + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sprycel (dasatinib) and Mekinist (trametinib) synergistically inhibited growth and induced apoptosis in a thyroid cancer cell line harboring HRAS G13R in culture (PMID: 27222538). | 27222538 |
| HRAS G13R | thyroid cancer | sensitive | Dasatinib + Selumetinib | Preclinical - Cell culture | Actionable | In a preclinical study, Sprycel (dasatinib) and Koselugo (selumetinib) synergistically inhibited growth and induced apoptosis in a thyroid cancer cell line harboring HRAS G13R in culture (PMID: 27222538). | 27222538 |
| HRAS G13R | rhabdomyosarcoma | sensitive | Ganitumab + Trametinib | Preclinical - Pdx | Actionable | In a preclinical study, Mekinist (trametinib) and Ganitumab (AMG-479) combination treatment resulted in tumor regression and increased progression-free survival in a patient-derived xenograft (PDX) model of rhabdomyosarcoma harboring HRAS G13R (PMID: 36322002). | 36322002 |
| HRAS G13R PTEN inact mut | Advanced Solid Tumor | predicted - sensitive | Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, cultured cells expressing HRAS G13R and PTEN inactivating mutations in the context of an HRAS, NRAS, and KRAS knockout were resistant to treatment with Zarnestra (tipifarnib) (Cancer Res 2022;82(12_Suppl):Abstract nr 1181). | detail... |
| HRAS G13R PTEN inact mut | Advanced Solid Tumor | predicted - sensitive | AZD8186 + Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, cultured cells expressing HRAS G13R and PTEN inactivating mutations in the context of an HRAS, NRAS, and KRAS knockout were sensitive to combined treatment with Zarnestra (tipifarnib) and AZD8186 (Cancer Res 2022;82(12_Suppl):Abstract nr 1181). | detail... |
| ALK F1245Y HRAS G13R | neuroblastoma | predicted - resistant | Lorlatinib | Case Reports/Case Series | Actionable | In a Phase I trial, a neuroblastoma patient harboring ALK F1245Y developed progressive disease on treatment with Lorbrena (lorlatinib) and was found to have acquired HRAS G13R via circulating tumor DNA (PMID: 37147298; NCT03107988). | 37147298 |
| HRAS G13V PIK3CA E545K | salivary gland carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a clinical case study, Zarnestra (tipifarnib) treatment resulted in a partial response and progression-free survival lasting more than 5 months in a patient with androgen-receptor (AR)-positive salivary duct carcinoma harboring HRAS G13V and PIK3CA E545K (PMID: 37427101). | 37427101 |
| HRAS Q61H | uterine cancer | sensitive | BTX-6654 | Preclinical - Cell culture | Actionable | In a preclinical study, BTX-6654 inhibited proliferation of a uterine cancer cell line harboring HRAS Q61H in 3D culture (PMID: 38224565). | 38224565 |
| HRAS Q61H | uterine cancer | sensitive | BTX-7312 | Preclinical - Cell culture | Actionable | In a preclinical study, BTX-7312 inhibited proliferation of a uterine cancer cell line harboring HRAS Q61H in 3D culture (PMID: 38224565). | 38224565 |
| HRAS Q61L | lung squamous cell carcinoma | no benefit | Buparlisib | Preclinical - Cell culture | Actionable | In a preclinical study, BKM120 did not inhibit growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture (PMID: 26544513) | 26544513 |
| HRAS Q61L | Advanced Solid Tumor | sensitive | Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing HRAS Q61L demonstrated sensitivity to growth inhibition by Afinitor (everolimus) in culture (PMID: 26544513). | 26544513 |
| HRAS Q61L | Advanced Solid Tumor | sensitive | Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing HRAS Q61L demonstrated sensitivity to growth inhibition by Binimetinib (MEK162) in culture (PMID: 26544513). | 26544513 |
| HRAS Q61L | lung squamous cell carcinoma | sensitive | Selumetinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Selumetinib (AZD6244) inhibited growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture, and inhibited tumor growth in xenograft models (PMID: 26544513). | 26544513 |
| HRAS Q61L | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, a head and neck squamous cell carcinoma cell line xenograft model harboring HRAS Q61L was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth and vessel formation, increased apoptotic activity, and decreased cell proliferation (PMID: 32727882). | 32727882 |
| HRAS Q61L | head and neck squamous cell carcinoma | sensitive | Sirolimus + Trametinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Rapamune (sirolimus) worked synergistically with Mekinist (trametinib) to inhibit proliferation of head and neck squamous carcinoma cell lines harboring HRAS Q61L in culture and to reduce tumor growth in cell line xenograft models (PMID: 26882569). | 26882569 |
| HRAS Q61L | skin squamous cell carcinoma | no benefit | PLX7904 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, PLX7904 did not stimulate growth of Zelboraf (vemurafenib)-induced cutaneous squamous cell carcinoma cells harboring HRAS Q61L in culture or in cell line xenograft models (PMID: 26466569). | 26466569 |
| HRAS Q61L | lung squamous cell carcinoma | sensitive | Everolimus + Selumetinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of Selumetinib (AZD6244) and Afinitor (everolimus) inhibited growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture, and inhibited tumor growth in xenograft models, with increased efficacy compared to either agent alone (PMID: 26544513). | 26544513 |
| HRAS Q61L | lung squamous cell carcinoma | sensitive | Binimetinib + Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture (PMID: 26544513). | 26544513 |
| HRAS Q61L | Advanced Solid Tumor | sensitive | Binimetinib + Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Binimetinib (MEK162) and Afinitor (everolimus) worked synergistically to inhibit growth of transformed cells expressing HRAS Q61L in culture (PMID: 26544513). | 26544513 |
| HRAS Q61L | lung squamous cell carcinoma | sensitive | AZD8055 + Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Binimetinib (MEK162) and AZD8055 reduced phosphorylation of ERK and S6 and worked synergistically to inhibit growth of a lung squamous cell carcinoma cell line harboring HRAS Q61L in culture (PMID: 26544513). | 26544513 |
| HRAS Q61L | Advanced Solid Tumor | sensitive | NS1 | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing HRAS Q61L demonstrated sensitivity to NS1, resulting in inhibition of Mapk and Akt signaling and cell transformation in culture (PMID: 27820802). | 27820802 |
| HRAS Q61L | head and neck squamous cell carcinoma | sensitive | SCH772984 + Tipifarnib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of SCH772984 sensitized head and neck squamous cell carcinoma cell lines harboring HRAS Q61L to treatment with Zarnestra (tipifarnib), resulting in enhanced growth inhibition and increased apoptosis in culture (PMID: 35247914). | 35247914 |
| HRAS Q61L | head and neck squamous cell carcinoma | sensitive | Tipifarnib + Ulixertinib | Preclinical - Cell culture | Actionable | In a preclinical study, combination treatment with Ulixertinib (BVD-523) and Zarnestra (tipifarnib) resulted in a synergistic effect, with enhanced apoptosis in a head and neck squamous cell carcinoma cell line harboring HRAS Q61L in culture (PMID: 35247914). | 35247914 |
| HRAS Q61L | esophageal cancer | sensitive | IHMT-RAF-128 | Preclinical - Cell culture | Actionable | In a preclinical study, IHMT-RAF-128 inhibited proliferation in an esophageal cancer cell line harboring HRAS Q61L in culture (PMID: 37164118). | 37164118 |
| HRAS Q61R | Advanced Solid Tumor | sensitive | Everolimus | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing HRAS Q61R demonstrated sensitivity to growth inhibition by Afinitor (everolimus) in culture (PMID: 26544513). | 26544513 |
| HRAS Q61R | Advanced Solid Tumor | sensitive | Binimetinib | Preclinical - Cell culture | Actionable | In a preclinical study, transformed cells expressing HRAS Q61R demonstrated sensitivity to growth inhibition by Binimetinib (MEK162) in culture (PMID: 26544513). | 26544513 |
| HRAS Q61R | bladder urothelial carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS mutations, 2 patients with bladder urothelial carcinoma harbored HRAS Q61R achieved partial responses (PMID: 32636318; NCT02535650). | 32636318 |
| HRAS K117N | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS K117N was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). | 32727882 |
| FGFR3 K650E FGFR3 over exp HRAS K117E | multiple myeloma | sensitive | PD173074 | Preclinical - Cell culture | Actionable | In a preclinical study, PD173074 inhibited Fgfr3 signaling, induced cell cycle arrest, and decreased proliferation of multiple myeloma cells harboring HRAS K117E and overexpression of FGFR3 K650E in culture (PMID: 22869148). | 22869148 |
| FGFR3 K650E FGFR3 over exp HRAS K117E | myeloid neoplasm | sensitive | AZ8010 | Preclinical | Actionable | In a preclinical study, AZ8010 inhibited Fgfr3 signaling and decreased proliferation of myeloma cells with HRAS K117E and overexpression of FGFR3 K650E in culture (PMID: 22869148). | 22869148 |
| HRAS 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 |
| HRAS act mut | transitional cell carcinoma | predicted - sensitive | Tipifarnib | Phase II | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated safety and preliminary efficacy in patients with metastatic urothelial carcinoma harboring HRAS mutations (n=14) or STK11:rs2075606, 3 of 4 patients achieved progression-free survival at 6 months harbored HRAS activating mutations, and no response was observed in HRAS wild-type patients (J Clin Oncol 38: 2020 (suppl; abstr 5086); NCT02535650). | detail... |
| HRAS act mut | salivary gland carcinoma | sensitive | Tipifarnib | Clinical Study | Actionable | In a clinical study, Zarnestra (tipifarnib) treatment resulted in an overall response rate of 8% (n=13) with one ongoing partial response with a duration of 14 months and stable disease as the best response in 58% (7/12) of evaluable patients with HRAS-mutant metastatic salivary gland carcinoma, and a median overall survival of 18 months, and a median progression-free survival of 7 months (PMID: 32557577). | 32557577 |
| EML4 - ALK HRAS amp | lung non-small cell carcinoma | predicted - resistant | Crizotinib | Case Reports/Case Series | Actionable | In a clinical study, a non-small cell lung carcinoma patient harboring EML4-ALK treated with Xalkori (crizotinib) responded, but eventually progressed, and was subsequently found to harbor a presumed resistance alteration, HRAS amplification (PMID: 29636358). | 29636358 |
| HRAS A146T | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, a head and neck squamous cell carcinoma patient-derived xenograft (PDX) model harboring HRAS A146T was sensitive to treatment with Zarnestra (tipifarnib), demonstrating inhibition of tumor growth, decreased cell proliferation, and reduced Erk activity (PMID: 32727882). | 32727882 |
| HRAS over exp | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, Zarnestra (tipifarnib) treatment resulted in tumor regression in patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma overexpressing wild-type Hras (J Clin Oncol 38: 2020 (suppl; abstr e15658)). | detail... |
| HRAS over exp | head and neck squamous cell carcinoma | sensitive | Alpelisib + Tipifarnib | Preclinical - Pdx & cell culture | Actionable | In a preclinical study, the combination of Piqray (alpelisib) and Zarnestra (tipifarnib) inhibited Mtor and Rsk phosphorylation, induced cell cycle arrest and apoptosis, and synergistically inhibited viability of an HRAS-overexpressing head and neck squamous cell carcinoma cell line in culture and inhibited tumor growth in patient-derived xenograft (PDX) models (PMID: 37339176). | 37339176 |
| HRAS over exp | head and neck squamous cell carcinoma | sensitive | Alpelisib + Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, Zarnestra (tipifarnib) and Piqray (Alpelisib) combination treatment resulted in enhanced tumor regression in patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma overexpressing wild-type Hras (J Clin Oncol 38: 2020 (suppl; abstr e15658)). | detail... |
| HRAS over exp | head and neck squamous cell carcinoma | predicted - sensitive | Tipifarnib + Uprosertib | Preclinical - Pdx | Actionable | In a preclinical study, Zarnestra (tipifarnib) and Uprosertib (GSK2141795) combination treatment resulted in enhanced tumor regression in patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma overexpressing wild-type Hras (J Clin Oncol 38: 2020 (suppl; abstr e15658)). | detail... |
| HRAS over exp | head and neck squamous cell carcinoma | predicted - sensitive | Sapanisertib + Tipifarnib | Preclinical - Pdx | Actionable | In a preclinical study, Zarnestra (tipifarnib) and Sapanisertib (MLN0128) combination treatment resulted in enhanced tumor regression in patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma overexpressing wild-type Hras (J Clin Oncol 38: 2020 (suppl; abstr e15658)). | detail... |
| HRAS V29Cfs*19 | bladder urothelial carcinoma | predicted - sensitive | Tipifarnib | Case Reports/Case Series | Actionable | In a Phase II trial, Zarnestra (tipifarnib) demonstrated manageable toxicity profile, resulted in an objective response rate of 33.3% (5/15) in patients with transitional cell carcinoma harboring HRAS mutations, a patient with bladder urothelial carcinoma harboring HRAS V29Cfs*19 achieved a partial response (PMID: 32636318; NCT02535650). | 32636318 |
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