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| Gene | HRAS |
| Variant | mutant |
| Impact List | unknown |
| Protein Effect | unknown |
| Gene Variant Descriptions | HRAS mutant indicates an unspecified mutation in the HRAS gene. |
| Associated Drug Resistance |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| 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 | 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 | 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 |
| 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 | 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 | 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 | 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 56% (10/18) in patients with head and neck squamous cell carcinoma harboring HRAS missense mutations at a variant allele frequency over 20%, with a median progression-free survival of 6.1 months (J Clin Oncol 38: 2020 (suppl; abstr 6504); NCT02383927). | detail... |
| 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 | 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 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) compared to placebo in thyroid medullary carcinoma patients harboring RAS mutations (PMID: 27525386). | 27525386 |
| 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 | 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 | 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 mut PIK3CA R88Q | malignant 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 | malignant 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 | malignant 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 |
| Molecular Profile | Protein Effect | Treatment Approaches |
|---|---|---|
| HRAS mutant | unknown | |
| HRAS mut PIK3CA R88Q | ||
| HRAS mut PIK3CA E542K | ||
| HRAS mut PIK3CA H1047R | ||
| HRAS mut PIK3CA M1043V |